Avery’s Diseases of the Newborn 2018

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Avery’s Diseases of the Newborn

Avery’s Diseases of the Newborn Tenth Edition

Christine A. Gleason, MD Professor of Pediatrics Division of Neonatology Department of Pediatrics University of Washington Seattle Children’s Hospital Seattle, Washington

Sandra E. Juul, MD, PhD W. Alan Hodson Endowed Chair in Pediatrics Professor of Pediatrics Chief, Division of Neonatology Department of Pediatrics University of Washington Seattle Children’s Hospital Seattle, Washington

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

AVERY’S DISEASES OF THE NEWBORN, TENTH EDITION

ISBN: 978-0-323-40139-5

Copyright © 2018 by Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the Publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted in 2012, 2005, 1998, 1991, 1984, 1977, 1971, 1965, 1960. Library of Congress Cataloging-in-Publication Data Names: Gleason, Christine A., editor. | Juul, Sandra E., editor. Title: Avery’s diseases of the newborn / [edited by] Christine A. Gleason, Sandra E. Juul. Other titles: Diseases of the newborn Description: Tenth edition. | Philadelphia, PA : Elsevier, [2018] | Includes bibliographical references and index. Identifiers: LCCN 2017019069 | ISBN 9780323401395 (hardcover : alk. paper) Subjects: | MESH: Infant, Newborn, Diseases Classification: LCC RJ254 | NLM WS 421 | DDC 618.92/01–dc23 LC record available at https://lccn.loc.gov/2017019069

Senior Content Strategist: Sarah Barth Senior Content Development Specialist: Deidre Simpson Publishing Services Manager: Patricia Tannian Senior Project Manager: Sharon Corell Book Designer: Bryan Salisbury

Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

To the babies—our patients—who humble and inspire us. To their families, who encourage us to keep moving our field forward. To neonatal caregivers everywhere, with gratitude for all you do.

Contributors

Steven H. Abman, MD Professor Department of Pediatrics University of Colorado Health Sciences Center Director Pediatric Heart Lung Center The Children’s Hospital Aurora, Colorado Karel Allegaert, MD, PhD Professor Department of Woman and Child KU Leuven Leuven, Belgium Consultant Department of Surgery and Intensive Care Erasmus MC-Sophia Children’s Hospital Rotterdam, The Netherlands Bhawna Arya, MD Assistant Professor Department of Pediatrics and Pediatric Cardiology University of Washington Seattle Children’s Hospital Seattle, Washington David Askenazi, MD, MSPH Associate Professor Department of Pediatrics University of Alabama at Birmingham Birmingham, Alabama Timur Azhibekov, MD Assistant Professor of Clinical Pediatrics Fetal and Neonatal Institute Division of Neonatology Children’s Hospital of Los Angeles Department of Pediatrics Keck School of Medicine University of Southern California, Los Angeles Los Angeles, California Stephen A. Back, MD, PhD Professor of Pediatrics and Neurology Oregon Health and Science University Clyde and Elda Munson Professor of Pediatric Research Director Neuroscience Section Papé Family Pediatric Research Institute Portland, Oregon

H. Scott Baldwin, MD Professor of Pediatrics and Cell and Developmental Biology Vanderbilt University Medical Center Chief Division of Pediatric Cardiology Co-Director Pediatric Heart Institute Monroe Carell Jr. Children’s Hospital at Vanderbilt Nashville, Tennessee Roberta A. Ballard, MD Professor Department of Pediatrics and Neonatology University of California, San Francisco, School of Medicine San Francisco, California Eduardo Bancalari, MD Professor of Pediatrics Director Division of Neonatology University of Miami Miller School of Medicine Chief Newborn Service Jackson Memorial Hospital Miami, Florida Carlton M. Bates, MD Professor of Pediatrics Vice Chair for Basic Research Department of Pediatrics University of Pittsburgh School of Medicine Chief of Pediatric Nephrology Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania Maneesh Batra, MD, MPH Associate Professor Department of Pediatrics University of Washington School of Medicine Seattle, Washington Cheryl B. Bayart, MD, MPH Department of Pediatric Dermatology University of Washington Seattle Children’s Hospital Seattle, Washington

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Contributors

Gary A. Bellus, MD, PhD Associate Professor Department of Pediatrics and Dermatology University of Colorado School of Medicine Aurora, Colorado Director Clinical Genetics and Genomic Medicine Geisinger Health System Danville, Pennsylvania

Maryse Bouchard, MD, MSc Associate Professor Orthopaedic Surgery University of Washington Pediatric Orthopedic Surgeon Department of Orthopedics and Sports Medicine Seattle Children’s Hospital Seattle, Washington

Thomas J. Benedetti, MD, MHA Professor Department of Obstetrics and Gynecology University of Washington School of Medicine Seattle, Washington

Heather A. Brandling-Bennett, MD Associate Professor Department of Pediatrics University of Washington Seattle Children’s Hospital Seattle, Washington

John T. Benjamin, MD, MPH Assistant Professor of Pediatrics Department of Pediatrics Division of Neonatology Vanderbilt University Medical Center Nashville, Tennessee

Darcy E. Broughton, MD Clinical Fellow Department of Obstetrics and Gynecology Division of Reproductive Endocrinology and Infertility Washington University in St. Louis St. Louis, Missouri

James T. Bennett, MD, PhD Assistant Professor of Pediatrics Division of Genetic Medicine Center for Developmental Biology and Regenerative Medicine Assistant Director Molecular Diagnostic Laboratories University of Washington Seattle Children’s Hospital Seattle, Washington

Zane Brown, MD Professor Division of Perinatology Department of Obstetrics and Gynecology Division of Women’s Health University of Washington Seattle, Washington

Gerard T. Berry, MD Harvey Levy Chair in Metabolism Director Metabolism Program Division of Genetics and Genomics Boston Children’s Hospital Professor of Pediatrics Harvard Medical School Boston, Massachusetts Gil Binenbaum, MD, MSCE Attending Surgeon Department of Ophthalmology The Children’s Hospital of Philadelphia Associate Professor of Ophthalmology Department of Ophthalmology Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania Markus D. Boos, MD, PhD Assistant Professor Department of Pediatrics Division of Dermatology University of Washington Seattle Children’s Hospital Seattle, Washington

Katherine H. Campbell, MD, MPH Assistant Professor Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine New Haven, Connecticut Suzan L. Carmichael, PhD, MS Professor Department of Pediatrics Stanford University Stanford, California Brian S. Carter, MD Professor of Pediatrics Division of Neonatology University of Missouri-Kansas City School of Medicine Bioethicist Bioethics Center Children’s Mercy Hospital Kansas City, Missouri Stephen Cederbaum, MD Research Professor Department of Psychiatry, Pediatrics, and Human Genetics University of California, Los Angeles Los Angeles, California

Contributors

Shilpi Chabra, MD Associate Professor Department of Pediatrics University of Washington and Seattle Children’s Hospital Seattle, Washington Justine Chang, MD Assistant Professor Department of Obstetrics and Gynecology University of Washington Seattle, Washington Edith Y. Cheng, MD, MS Professor Chief of Service Obstetrics Division Chief Maternal Fetal Medicine Department of Maternal Fetal Medicine and Medical Genetics University of Washington Seattle, Washington Karen M. Chisholm, MD, PhD Anatomic Pathologist Department of Laboratories Seattle Children’s Hospital Clinical Assistant Professor Department of Laboratory Medicine University of Washington Seattle, Washington Robert D. Christensen, MD Robert L. Jung Presidential Chair Professor and Division Chief Division of Neonatology Professor Division of Hematology/Oncology University of Utah School of Medicine Director of Research Department of Women and Newborns Intermountain Healthcare Salt Lake City, Utah Terrence Chun, MD Associate Professor of Pediatrics Department of Pediatrics University of Washington Seattle, Washington Nelson Claure, MSc, PhD Research Associate Professor Director Neonatal Pulmonary Research Laboratory Department of Pediatrics Division of Neonatology University of Miami Miller School of Medicine Miami, Florida

Ronald I. Clyman, MD Professor of Pediatrics and Senior Staff Cardiovascular Research Institute University of California, San Francisco San Francisco, California Tarah T. Colaizy, MD, MPH Associate Professor of Pediatrics Stead Department of Pediatrics University of Iowa Iowa City, Iowa DonnaMaria E. Cortezzo, MD Assistant Professor Pediatrics and Anesthesiology Division of Neonatology and Pulmonary Biology Division of Pediatric Palliative Care Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio C. Michael Cotten, MD, NHS Professor of Pediatrics Department of Pediatrics and Neonatology Duke University School of Medicine Durham, North Carolina Michael L. Cunningham, MD, PhD Professor and Chief Division of Craniofacial Medicine Department of Pediatrics University of Washington Medical Director Craniofacial Center Seattle Children’s Hospital Seattle, Washington Alejandra G. de Alba Campomanes, MD, MPH Associate Professor of Clinical Ophthalmology and Pediatrics Department of Ophthalmology University of California, San Francisco San Francisco, California Ellen Dees, MD Assistant Professor of Pediatrics Pediatric Cardiology Training Program Vanderbilt Children’s Hospital Nashville, Tennessee Sara B. DeMauro, MD, MSCE Assistant Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Program Director Neonatal Follow-Up and Attending Neonatologist The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Scott C. Denne, MD Professor of Pediatrics Department of Pediatrics Indiana University Indianapolis, Indiana

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Contributors

Emöke Deschmann, MD, MMSc Faculty/Attending Neonatologist Department of Women’s and Children’s Health Division of Neonatology Karolinska Institute Department of Neonatology Karolinska University Hospital Stockholm, Sweden Carolina Cecilia DiBlasi, MD Clinical Assistant Professor Division of Endocrinology and Diabetes University of Washington Seattle Children’s Hospital Seattle, Washington Robert M. DiBlasi, RRT-NPS, FAARC Respiratory Research Coordinator Center for Developmental Therapeutics Seattle Children’s Research Institute Seattle, Washington Reed A. Dimmitt, MD, MSPH Associate Professor of Pediatrics and Surgery Director Division of Neonatology and Pediatric Gastroenterology and Nutrition University of Alabama at Birmingham Birmingham, Alabana Sara A. DiVall, MD Assistant Professor Department of Pediatrics and Endocrinology University of Washington Seattle, Washington Orchid Djahangirian, BSc, MD, FRCSC Fellow Department of Pediatric Urology University of California, Irvine Irvine, California Dan Doherty, MD, PhD Professor Department of Pediatrics University of Washington Seattle Children’s Hospital Seattle, Washington Eric C. Eichenwald, MD Professor of Pediatrics Department of Pediatrics Perelman School of Medicine at the University of Pennsylvania Chief Division of Neonatology Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Rachel Engen, MD Ann and Robert H. Lurie Children’s Hospital of Chicago Chicago, Illinois

Cyril Engmann, MBBS, FAAP Attending Neonatologist and Professor Department of Pediatrics and Global Health University of Washington Schools of Medicine and Public Health Global Program Leader and Director Maternal, Newborn, Childhealth, and Nutrition PATH Seattle, Washington Jacquelyn R. Evans, MD Associate Division Chief of Neonatology Department of Pediatrics Children’s Hospital of Phildelphia and Perelman School of Medicine at the University of Pennsylvania Chair The Children’s Hospital Neonatal Consortium Philadelphia, Pennsylvania Kelly N. Evans, MD Assistant Professor Department of Pediatrics University of Washington Craniofacial Center Seattle Children’s Hospital Seattle, Washington Diana L. Farmer, MD, FACS, FRCS Professor and Chair Surgeon-in-Chief Department of Surgery University of California, Davis Sacramento, California Patricia Y. Fechner, MD Medical Director DSD Program Seattle Children’s Hospital Professor Department of Pediatric Endocrinology University of Washington School of Medicine Seattle, Washington Patricia Ferrieri, MD Chairman’s Fund Endowed Professor in Laboratory Medicine and Pathology Professor Department of Pediatrics Division of Infectious Diseases University of Minnesota Medical School Director Infectious Diseases Diagnostic Laboratory University of Minnesota Medical Center Minneapolis, Minnesota Neil N. Finer, MD Division of Neonatal-Perinatal Medicine Department of Pediatrics University of California, San Diego San Diego, California

Contributors

Rachel A. Fleishman, MD Penn Medical Clinician University of Pennsylvania School of Medicine Attending Neonatologist CHOP Newborn Care Network Children’s Hospital of Pennsylvania Philadelphia, Pennsylvania Bobbi Fleiss, PhD Division of Imaging Sciences and Biomedical Engineering King’s College London London, Great Britain Joseph T. Flynn, MD, MS Dr. Robert O. Hickman Endowed Chair in Pediatric Nephrology Professor of Pediatrics University of Washington Chief Division of Nephrology Seattle Children’s Hospital Seattle, Washington Katherine T. Flynn-O’Brien, MD, MPH Resident Physician Department of Surgery University of Washington Seattle, Washington Mark R. Frey, PhD Associate Professor Department of Pediatrics, and Biochemistry and Molecular Medicine The Saban Research Institute of Children’s Hospital University of Southern California, Los Angeles Los Angeles, California Lydia Furman, MD Professor of Pediatrics Rainbow Babies and Children’s Hospital Co-Chair UHCMC Institutional Review Board Case Western Reserve University School of Medicine Cleveland, Ohio Renata C. Gallagher, MD, PhD Professor of Clinical Pediatrics Department of Pediatrics University of California, San Francisco San Francisco, California

Michael J. Goldberg, MD Clinical Professor Department of Orthopaedics and Sports Medicine University of Washington Seattle Children’s Hospital Seattle, Washington Adam B. Goldin, MD, MPH Associate Professor Department of Pediatric General and Thoracic Surgery University of Washington Seattle Children’s Hospital Seattle, Washington Sidney M. Gospe, Jr., MD, PhD Herman and Faye Sarkowsky Endowed Chair of Child Neurology Professor Department of Neurology and Pediatrics University of Washington Head Division of Neurology Seattle Children’s Hospital Seattle, Washington Pierre Gressens, MD, PhD Research Officer and Director Robert-Debre Hospital Paris, France Deepti Gupta, MD Assistant Professor Department of Pediatrics Division of Dermatology University of Washington Seattle Children’s Hospital Seattle, Washington Susan H. Guttentag, MD Julia Carell Stadler Professor of Pediatrics Department of Pediatrics Division of Neonatology Monroe Carell, Jr., Children’s Hospital at Vanderbilt Nashville, Tennessee Chad R. Haldeman-Englert, MD Clinical Geneticist Fullerton Genetics Center Asheville, North Carolina

Estelle B. Gauda, MD Professor of Pediatrics Department of Pediatrics The Johns Hopkins University School of Medicine Baltimore, Maryland

Thomas N. Hansen, MD Senior Investigator Center for Developmental Therapeutics Seattle Children’s Research Institute Seattle, Washington

Christine A. Gleason Professor of Pediatrics Division of Neonatology Department of Pediatrics University of Washington Seattle Children’s Hospital Seattle, Washington

Anne V. Hing, MD Professor Department of Pediatrics University of Washington Seattle, Washington

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Contributors

Sangeeta Hingorani, MD, MPH Associate Professor Department of Pediatrics University of Washington Seattle Children’s Hospital Assistant Member Clinical Research Division Fred Hutchinson Cancer Research Center Seattle, Washington Susan R. Hintz, MD, MS Robert L. Hess Family Professor Professor of Pediatrics, and Obstetrics and Gynecology Associate Chief for Prenatal Services Division of Neonatal and Developmental Medicine Stanford University School of Medicine Medical Director Fetal and Pregnancy Health Program Lucile Packard Children’s Hospital Palo Alto, California Shinjiro Hirose, MD Associate Professor and Division Chief Pediatric General, Thoracic, and Fetal Surgery Department of Surgery University of California, Davis Sacramento, California W. Alan Hodson, MMSc, MD Professor Emeritus Department of Pediatrics University of Washington Seattle, Washington Kara K. Hoppe, DO Department of Obstetrics and Gynecology Maternal Fetal Medicine University of Wisconsin-Madison Madison, Wisconsin Margaret K. Hostetter, MD BK Rachford Professor and Chair Department of Pediatrics Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio Benjamin Huang, MD Clinical Instructor Department of Pediatrics University of California, San Francisco San Francisco, California Sarah Bauer Huang, MD, PhD Child Neurology Resident Department of Neurology University of Washington Seattle, Washington

Terrie E. Inder, MBChB, MD Cristian Ionita Department of Neurology University of Washington Seattle Children’s Hospital Seattle, Washington Cristian Inoita, MD Clinical Associate Professor Department of Pediatrics Yale University School of Medicine New Haven, Connecticut J. Craig Jackson, MD, MHA Professor Department of Pediatrics University of Washington Seattle Children’s Hospital Seattle, Washington Deepak Jain, MD Assistant Professor of Pediatrics Department of Pediatrics Division of Neonatology University of Miami Miller School of Medicine Jackson Memorial Hospital Miami, Florida Lucky Jain, MD, MBA Richard W. Blumberg Professor and Chairman Department of Pediatrics Emory University School of Medicine Chief Academic Officer Children’s Healthcare of Atlanta Atlanta, Georgia Patrick J. Javid, MD Associate Professor of Surgery Department of Surgery University of Washington Pediatric Surgeon Seattle Children’s Hospital Seattle, Washington Cassandra D. Josephson, MD Associate Professor Pathology and Pediatrics Director Clinical Research Department of Pathology Center for Transfusion and Cellular Therapies Director Transfusion Medicine Fellowship Program Department of Pathology Center for Transfusion and Cellular Therapies Emory University School of Medicine Medical Director Pathology Department Blood and Tissue Services Children’s Healthcare of Atlanta Atlanta, Georgia

Contributors

Emily S. Jungheim, MD, MSCI Assistant Professor Department of Obstetrics and Gynecology Division of Reproductive Endocrinology and Infertility Washington University in St. Louis St. Louis, Missouri Sandra E. Juul, MD, PhD W. Alan Hodson Endowed Chair in Pediatrics Professor of Pediatrics Chief Division of Neonatology Department of Pediatrics University of Washington Seattle Children’s Hospital Seattle, Washington Anup Katheria, MD, FAACP Assistant Professor of Pediatrics Department of Pediatrics Loma Linda University Loma Linda, California Director Neonatal Research Institute Sharp Mary Birch Hospital for Women and Newborns San Diego, California Benjamin A. Keller, BS, MD Chief Surgical Resident Department of Surgery University of California, Davis Sacramento, California Roberta L. Keller, MD Professor of Clinical Pediatrics Vice Chair Clinical Translational Research Director of Neonatal Research Director Neonatal ECMO Program Director of Neonatal Services Fetal Treatment Center UCSF Benioff Children’s Hospital University of California, San Francisco San Francisco, California Thomas F. Kelly, MD Clinical Professor and Chief Division of Perinatal Medicine Department of Reproductive Medicine University of California, San Diego School of Medicine La Jolla, California Director of Maternity Services University of California, San Diego Medical Center San Diego, California Kate Khorsand, MD Department of Pediatrics Division of Dermatology Seattle Children’s Hospital Seattle, Washington

Grace Kim, MD, MS Assistant Professor Department of Endocrinology Seattle Children’s Hospital Seattle, Washington John P. Kinsella, MD Professor Department of Pediatrics University of Colorado School of Medicine Children’s Hospital Colorado Aurora, Colorado Ildiko H. Koves, MD, FRACP Associate Professor Department of Endocrinology and Diabetes Seattle Children’s Hospital Seattle, Washington Christina Lam, MD Assistant Professor Biochemical Genetics Department of Pediatrics Division of Genetic Medicine University of Washington Seattle Children’s Hospital Seattle, Washington Guest Researcher NIH, NHGRI Bethesda, Maryland Erin R. Lane, MD Fellow Pediatric Gastroenterology University of Washington Seattle, Washington John D. Lantos, MD Professor Department of Pediatrics University of Missouri–Kansas City Kansas City, Missouri Daniel J. Ledbetter, MD Professor Department of Surgery University of Washington Attending Surgeon Department of Pediatric General and Thoracic Surgery Seattle Children’s Hospital Seattle, Washington Ben Lee, MD, MPH, MSCR Associate Professor of Clinical Pediatrics Weill Cornell Medicine-Qatar Medical Director of Operations Division of Neonatal and Perinatal Medicine Sidra Medical and Research Center Doha, Qatar

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Contributors

Harvey L. Levy, MD Senior Physician in Medicine/Genetics Division of Genetics and Genomics Boston Children’s Hospital Professor of Pediatrics Harvard Medical School Boston, Massachusetts Ofer Levy, MD, PhD Principal Investigator Precision Vaccines Program Division of Infectious Diseases Boston Children’s Hospital Associate Professor Department of Human Biology and Translational Medicine Harvard Medical School Boston, Massachusetts Mark B. Lewin, MD Professor and Division Chief Department of Pediatric Cardiology University of Washington School of Medicine Seattle, Washington David B. Lewis, MD Professor of Pediatrics Chief Division of Immunology and Allergy Department of Pediatrics Stanford University School of Medicine Stanford, California Attending Physician Lucile Salter Packard Children’s Hospital Palo Alto, California P. Ling Lin, MD, MSc Associate Professor Director Pediatric Infectious Diseases Fellowship Program Department of Pediatrics Division of Infectious Diseases Children’s Hospital of Pittsburgh of UPMC University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Tiffany Fangtse Lin, MD Pediatric Hematology Oncology Adjunct Instructor Department of Pediatrics University of California, San Francisco San Francisco, California Scott A. Lorch, MD, MSCE Associate Professor Department of Pediatrics Perelman School of Medicine of the University of Pennsylvania Harriet and Ronald Lassin Endowed Chair in Pediatric Neonatology Director Neonatal-Perinatal Medicine Fellowship Division of Neonatology Director Center for Perinatal and Pediatric Health Disparities Research The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Akhil Maheshwari, MD Professor of Pediatrics and Molecular Medicine Pamela and Leslie Muma Endowed Chair in Neonatology Chief Division of Neonatology Assistant Dean Graduate Medical Education Department of Pediatrics University of South Florida Tampa, Florida Emin Maltepe, MD, PhD Associate Professor Department of Pediatrics, Biomedical Sciences, and Developmental and Stem Cell Biology Division of Neonatology University of California, San Francisco San Francisco, California Ketzela J. Marsh, MS, MD Fellow in Pediatric and Adult Infectious Diseases University of Minnesota Medical School and Masonic Children’s Hospital Minneapolis, Minnesota Richard J. Martin, MBBS Professor Department of Pediatrics, Reproductive Biology, and Physiology and Biophysics Case Western Reserve University School of Medicine Drusinsky/Fanaroff Professor Department of Pediatrics Rainbow Babies and Children’s Hospital Cleveland, Ohio Dennis E. Mayock, BS, MD Professor Department of Pediatrics University of Washington Seattle, Washington Ryan Michael McAdams, MD Associate Professor Department of Pediatrics University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Irene McAleer, MD, JD, MBA Health Sciences Clinical Professor of Urology Departments of Urology and Pediatric Urology University of California, Irvine Irvine, California Steven J. McElroy, MD Associate Professor Interim Division Director Departments of Pediatrics, and Microbiology and Immunology University of Iowa Iowa City, Iowa

Contributors

Kera M. McNelis, MD Fellow Department of Neonatology Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio Patrick McQuillen, MD Professor of Pediatrics & Neurology Department of Pediatrics University of California, San Francisco San Francisco, California William L. Meadow, MD, PhD Professor Department of Pediatrics University of Chicago Chicago, Illinois Paul A. Merguerian, MD, MS Professor Department of Urology University of Washington Chief Division of Urology Seattle Children’s Hospital Seattle, Washington Lina Merjaneh, MD Assistant Professor Department of Pediatrics and Endocrinology University of Washington Seattle, Washington J. Lawrence Merritt, II, MD Associate Professor Department of Pediatrics University of Washington Seattle, Washington Valerie Mezger, PhD CNRS Epigenetics and Cell Fate Univ Paris Diderot, Sorbonne Paris Cité Département Hospitalo-Universitaire PROTECT Paris, France Marian G. Michaels, MD, MPH Professor of Pediatrics and Surgery Division of Pediatric Infectious Diseases Children’s Hospital of Pittsburgh of UPMC Professor of Pediatrics and Surgery University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

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Steven P. Miller, MDCM, MAAS Division Head Department of Pediatrics Division of Neurology The Hospital for Sick Children Professor of Pediatrics Department of Pediatrics University of Toronto Senior Scientist Neuroscience and Mental Health Sick Kids Research Institute Chair in Pediatric Neuroscience Bloorview Children’s Hospital Toronto, Ontario, Canada Sowmya S. Mohan, MD Assistant Professor Department of Pediatrics Division of Neonatal-Perinatal Medicine Emory University Atlanta, Georgia Thomas J. Mollen, MD Clinical Associate Department of Pediatrics Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania Thomas R. Moore, MD Professor of Maternal and Fetal Medicine CEO Faculty Practice Dean for Clinical Affairs University of California, San Diego San Diego, California Jeffrey C. Murray, MD Professor Department of Pediatrics The University of Iowa Iowa City, Iowa Karen F. Murray, MD Chief Division of Gastroenterology and Hepatology Department of Pediatrics Seattle Children’s Hospital Seattle, Washington Debika Nandi-Munshi, MD Assistant Clinical Professor Department of Pediatric Endocrinology and Diabetes Seattle Children’s Hospital University of Washington Seattle, Washington Niranjana Natarajan, MD Assistant Professor Department of Neurology Division of Child Neurology University of Washington Seattle, Washington

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Contributors

Jeffrey J. Neil, MD, PhD Professor of Neurology Department of Neurology Boston Children’s Hospital Boston, Massachusetts Kathryn D. Ness, MD, MSCI Clinical Associate Professor Department of Pediatrics Seattle Children’s Hospital Seattle, Washington Josef Neu, MD Professor Department of Pediatrics University of Florida Gainesville, Florida Angel Siu-Ying Nip, MBChB Fellow Department of Endocrinology Seattle Children’s Hospital Seattle, Washington Shahab Noori, MD Associate Professor of Pediatrics Fetal and Neonatal Institute Division of Neonatology Children’s Hospital Los Angeles Department of Pediatrics Keck School of Medicine University of Southern California Los Angeles, California Lila O’Mahony, MD Clinical Assistant Professor Department of Pediatric Emergency Medicine University of Washington Seattle Children’s Hospital Seattle, Washington Jonathan P. Palma, MD, MS Clinical Assistant Professor Department of Pediatrics Stanford University School of Medicine Medical Director of Clinical Informatics Stanford Children’s Health Clinical Informatics Fellowship Program Director Stanford Medicine Palo Alto, California Nigel Paneth, MD, MPH University Distinguished Professor Department of Epidemiology and Biostatistics and Pediatrics and Human Development Michigan State University East Lansing, Michigan

Thomas A. Parker, MD Professor Department of Pediatrics University of Colorado School of Medicine Children’s Hospital of Colorado Aurora, Colorado Ravi Mangal Patel, MD Associate Professor Department of Pediatrics Emory University School of Medicine Children’s Healthcare of Atlanta Atlanta, Georgia Anna A. Penn, MD, PhD Associate Professor Department of Pediatrics George Washington University School of Medicine Attending Physician Director of Translational Research for Hospital-Based Services Co-Director of Cerebral Palsy Prevention Program Fetal and Transitional Medicine, Neonatology Children’s National Medical Center Investigator Children’s Research Institute Center for Neuroscience Children’s National Medical Center Washington, DC Christian M. Pettker, MD Associate Professor Department of Obstetrics, Gynecology, and Reproductive Sciences Yale University School of Medicine New Haven, Connecticut Shabnam Peyvandi, MD Assistant Professor of Pediatrics Department of Pediatric Cardiology University of California, San Francisco Benioff Children’s Hospital San Francisco, California Cate Pihoker, MD Professor of Pediatrics Department of Endocrinology and Diabetes University of Washington Seattle Children’s Hospital Seattle, Washington Erin Plosa, MD Assistant Professor of Pediatrics Department of Pediatrics Vanderbilt University Nashville, Tennessee Brenda B. Poindexter, MD, MS Associate Professor of Pediatrics Section of Neonatal-Perinatal Medicine Indiana University School of Medicine Indianapolis, Indiana

Contributors

Michael A. Posencheg, MD Medical Director Intensive Care Nursery Neonatology and Newborn Services Hospital of the University of Pennsylvania Associate Professor of Clinical Pediatrics Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania Benjamin E. Reinking, BA, MD Clinical Professor of Pediatrics Stead Family Department of Pediatrics University of Iowa Carver College of Medicine Iowa City, Iowa Samuel Rice-Townsend, MD Attending Surgeon Department of Surgery Boston Children’s Hospital Assistant Professor Harvard Medical School Boston, Massachusetts

Mark D. Rollins, MD, PhD Professor Director Obstetric and Fetal Anesthesia Department of Anesthesia and Perioperative Care Department of Surgery Department of Obstetrics, Gynecology, and Reproductive Sciences University of California, San Francisco San Francisco, California Mark A. Rosen, MD Professor Emeritus Department of Anesthesia and Perioperative Care Department of Obstetrics, Gynecology, and Reproductive Sciences University of California, San Francisco San Francisco, California Courtney K. Rowe, MD Pediatric Urology Fellow University of Washington Seattle, Washington

Morgan K. Richards, MD, MPH Resident Department of Surgery University of Washington Seattle, Washington

Inderneel Sahai, MD Chief Medical Officer New England Newborn Screening Program University of Massachusetts Worcester, Massachusetts

C. Peter Richardson, PhD Associate Research Professor Department of Pediatrics University of Washington Department of Pulmonary and Newborn Care Seattle Children’s Hospital Principal Investigator Center for Developmental Therapy Seattle Children’s Research Institute Seattle, Washington

Sulagna C. Saitta, MD, PhD Director Clinical Genetics Center for Personalized Medicine Department of Pathology Children’s Hospital Los Angeles Associate Professor of Clinical Pathology Department of Pathology Keck School of Medicine of USC Los Angeles, California

Kelsey Richardson, MD Pediatric Nephrology Fellow Department of Nephrology Seattle Children’s Hospital Seattle, Washington

Parisa Salehi, MD Assistant Professor of Pediatrics Division of Endocrinology University of Washington Seattle Children’s Hospital Seattle, Washington

Kevin M. Riggle, MD Resident Department of Surgery University of Washington Seattle, Washington Elizabeth Robbins, MD Clinical Professor Department of Pediatrics University of California, San Francisco San Francisco, California

Pablo Sanchez, MD Professor of Pediatrics Nationwide Children’s Hospital The Ohio State University College of Medicine Divisions of Neonatal-Perinatal Medicine and Pediatric Infectious Diseases Director Clinical and Translational Research (Neonatology) Center for Perinatal Research The Research Institute at Nationwide Children’s Hospital Columbus, Ohio

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Matthew A. Saxonhouse, MD Associate Professor Division of Neonatology Department of Pediatrics Levine Children’s Hospital at Carolinas Medical Center University of North Carolina Charlotte Campus Charlotte, North Carolina Richard J. Schanler, MD, FAAP Associate Chairman Director Neonatal Services Cohen Children’s Medical Center Northwell Health Professor Department of Pediatrics Hofstra Northwell School of Medicine New Hyde Park, New York Mark R. Schleiss, MD American Legion and Auxiliary Heart Research Foundation Endowed Chair Department of Pediatrics Professor and Director Division of Pediatric Infectious Diseases and Immunology Co-Director Center for Infectious Diseases and Microbiology Translational Research University of Minnesota Medical School Minneapolis, Minnesota Thomas Scholz, MD Professor of Pediatrics Stead Family Department of Pediatrics University of Iowa College of Medicine Iowa City, Iowa Andrew L. Schwaderer, MD Pediatric Nephrologist Nationwide Children’s Hospital Columbus, Ohio David Selewski, MD, MS Assistant Professor Department of Pediatrics University of Michigan Ann Arbor, Michigan Zachary M. Sellers, MD, PhD Fellow Pediatric Gastroenterology, Hepatology, and Nutrition LeRoy Matthews Physician-Scientist Cystic Fibrosis Foundation Lucile Packard Children’s Hospital Stanford University School of Medicine Stanford, California

Istvan Seri, MD, PhD, HonD Professor Semmelweis University Faculty of Medicine First Department of Pediatrics Budapest, Hungary Keck School of Medicine University of Southern California Children’s Hospital Los Angeles Los Angeles, California Margarett Shnorhavorian, MD, MPH, FAAP, FACS Surgical Director DSD Program Director Research Division of Urology Seattle Children’s Hospital Assistant Professor of Urology University of Washington Seattle, Washington Eric Sibley, MD, PhD Associate Professor of Pediatrics Assistant Dean for Academic Advising Associate Chair for Academic Affairs Department of Pediatrics Stanford University School of Medicine Stanford, California Member The Child Health Research Institute Robert Sidbury, MD, MPH Professor Department of Pediatrics Chief Division of Dermatology University of Washington Seattle Children’s Hospital Seattle, Washington Rebecca Simmons, MD Hallam Hurt Professor of Pediatrics Department of Pediatrics Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Caitlin Smith, MD Fellow Department of Pediatric Surgery Seattle Children’s Hospital Seattle, Washington Martha C. Sola-Visner, MD Assistant Professor of Pediatrics Department of Medicine Division of Newborn Medicine Children’s Hospital Boston and Harvard Medical School Boston, Massachusetts

Contributors

Lakshmi Srinivasan, MBBS Clinical Associate Department of Pediatrics The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Robin H. Steinhorn, MD Senior Vice President Children’s National Health System Professor of Pediatrics George Washington University Washington, DC David K. Stevenson, MD Harold K. Faber Professor of Pediatrics Division of Neonatal and Developmental Medicine Stanford University Stanford, California Helen Stolp, BSc(Hons), PhD Perinatal Imaging and Health King’s College London London, Great Britain Craig Taplin, MBBS, FRACP Associate Professor of Pediatrics Division of Endocrinology and Diabetes University of Washington Seattle Children’s Hospital Seattle, Washington Peter Tarczy-Hornoch, MD Chair and Professor Biomedical Informatics and Medical Education Professor Department of Pediatrics Adjunct Professor Computer Science and Engineering University of Washington Seattle, Washington James A. Taylor, MD Child Health Institute University of Washington Seattle, Washington Janet A. Thomas, MD Associate Professor Department of Pediatrics University of Colorado School of Medicine Children’s Hospital Colorado Aurora, Colorado Tracy Thompson, MPH Program Director Department of Epidemiology and Biostatics College of Human Medicine Michigan State University East Lansing, Michigan

George E. Tiller, MD, PhD Regional Chief Department of Genetics Southern California Permanente Medical Group Co-Chair Interregional Genetics Workgroup Los Angeles, California Benjamin A. Torres, MD Associate Professor Department of Pediatrics Division of Neonatology University of South Florida Medical Director Jennifer Leigh Muma NICU Tampa General Hospital Tampa, Florida Christopher Michael Traudt, MD Assistant Professor Department of Pediatrics University of Washington Seattle, Washington John N. van den Anker , MD, PhD Chief Clinical Pharmacology Department of Pediatrics Children’s National Health System Washington, DC Chair Paediatric Pharmacology and Pharmacometrics Department of Pediatrics University Children’s Hospital Basel Basel, Switzerland Adjunct Faculty Intensive Care Department of Pediatric Surgery Erasmus Medical Center-Sophia Children’s Hospital Rotterdam, The Netherlands Margaret M. Vernon, MD Assistant Professor Department of Pediatrics Division of Cardiology University of Washington Seattle Children’s Hospital Seattle, Washington Betty Vohr, MD Director of Neonatal Follow-Up Department of Neonatology Women and Infants Hospital Professor of Pediatrics Department of Pediatrics Alpert Medical School of Brown University Providence, Rhode Island

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Contributors

Valencia P. Walker, MD Associate Clinical Professor Department of Pediatrics Co-Chairperson Pediatric Faculty Committee on Diversity Division of Neonatology David Geffen School of Medicine at UCLA Los Angeles, California Linda D. Wallen, MD Clinical Professor of Pediatrics Associate Division Head for Clinical Operations Division of Neonatology Department of Pediatrics University of Washington Seattle Children’s Hospital Seattle, Washington

Joern-Hendrik Weitkamp, MD Associate Professor of Pediatrics Department of Pediatrics Vanderbilt University Medical Center Nashville, Tennessee David Werny, MD, MPH Assistant Professor of Pediatrics Division of Endocrinology and Diabetes University of Washington Seattle Children’s Hospital Seattle, Washington

Matthew B. Wallenstein, MD Obstetrics and Gynecology Stanford, California

Klane K. White, MD, MSc Associate Professor Orthopaedic Surgery University of Washington Pediatric Orthopedic Surgeon Department of Orthopedic Surgery and Sports Medicine Seattle Children’s Hospital Seattle, Washington

Peter (Zhan Tao) Wang, BSc, MD, FRCSD Assistant Professor Schulich School of Medicine and Dentistry Western University London, Ontario, Canada

Laurel Willig, MD, MS Assistant Professor Department of Pediatrics Children’s Mercy Hospital Kansas City, Missouri

Bradley A. Warady, MD Professor of Pediatrics Department of Pediatrics University of Missouri-Kansas City School of Medicine Senior Associate Chairman Chief Section of Nephrology Director Dialysis and Transplantation Department of Pediatrics Children’s Mercy Hospitals and Clinics Kansas City, Missouri

David Woodrum, BA, MD Emeritus Professor Department of Pediatrics University of Washington Seattle, Washington

Robert M. Ward, MD Professor Emeritus Department of Pediatrics University of Utah Salt Lake City, Utah Jon F. Watchko, BS, MD Professor of Pediatrics, Obstetrics, Gynecology, and Reproductive Sciences Division of Newborn Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Elias Wehbi, BSc, MSc, MD, FRCSC Assistant Professor Department of Urology Division of Pediatric Urology University of California, Irvine Orange, California

George A. Woodward, MD, MBA Professor Department of Pediatrics Seattle Children’s Hospital Seattle, Washington Clyde J. Wright, MD Assistant Professor Section of Neonatology Department of Pediatrics University of Colorado School of Medicine Aurora, Colorado Jeffrey A. Wright, MD Associate Professor Department of General Pediatrics University of Washington Seattle, Washington Karyn Yonekawa, MD Associate Clinical Professor University of Washington Seattle Children’s Hospital Seattle, Washington Elaine H. Zackai, MD Division of Genetics Department of Pediatrics The Children’s Hospital of Pennsylvania Philadelphia, Pennsylvania

Preface

“The neonatal period … represents the last frontier of medicine, territory which has just begun to be cleared of its forests and underbrush in preparation for its eagerly anticipated crops of saved lives.” Introduction to the first edition of Schaffer’s Diseases of the Newborn

History The first edition of Diseases of the Newborn was published in 1960 by Dr. Alexander J. Schaffer, a well-known Baltimore pediatrician who coined the term neonatology to describe this emerging pediatric subspecialty that concentrated on “the art and science of diagnosis and treatment of disorders of the newborn infant.” Schaffer’s first edition was used mainly for diagnosis, but also included descriptions of new neonatal care practices (i.e., the use of antibiotics, temperature regulation, and attention to feeding techniques)—practices that had led to a remarkable decrease in the infant mortality rate in the United States, from 47 deaths per 1000 live births in 1940 to 26 per 1000 in 1960. But a pivotal year for the fledgling subspecialty of neonatology came 3 years later in 1963, with the birth of President John F. Kennedy’s son, Patrick Bouvier Kennedy, at 35 weeks’ gestation (i.e., late preterm). His death at 3 days of age, from complications of hyaline membrane disease, accelerated the development of infant ventilators that, coupled with micro-blood gas analysis and expertise in the use of umbilical artery catheterization, led to the development of intensive care for newborns in the 1960s on both sides of the Atlantic. Advances in neonatal surgery and cardiology, along with further technological innovations, stimulated the development of neonatal intensive care units and regionalization of care for sick newborn infants over the next several decades. These developments were accompanied by an explosion of neonatal research activity that led to improved understanding of the pathophysiology and genetic basis of diseases of the newborn, which in turn has led to spectacular advances in neonatal diagnosis and therapeutics—particularly in the care of preterm infants. Combined, these efforts led to continued improvements in the infant mortality rate in the United States, from 26 deaths per 1000 live births in 1960 to 5.8 deaths per 1000 live births in 2014. Current research efforts are focused on decreasing the striking regional, ethnic, and global disparities in infant mortality rates, improving neonatal outcomes, advancing neonatal therapeutics, preventing newborn diseases, and finally—teaming with our obstetrical colleagues—preventing prematurity. We neonatologists would like to begin downsizing, instead of continually expanding, our neonatal intensive care units! Dr. Mary Ellen Avery joined Dr. Schaffer for the third edition of Diseases of the Newborn in 1971. For the fourth edition in 1977, Drs. Avery and Schaffer recognized that their book now needed multiple contributors with subspecialty expertise and they became co-editors, rather than sole co-authors, of the book. In the preface

to that fourth edition, Dr. Schaffer wrote, “We have also seen the application of some fundamental advances in molecular biology to the management of our fetal and newborn patients”—referring to the new knowledge of hemoglobinopathies. Dr. Schaffer died in 1981 and Dr. H. William Taeusch joined Dr. Avery as co-editor for the fifth edition in 1984. Dr. Roberta Ballard joined Drs. Taeusch and Avery for the sixth edition in 1991, with the addition of Dr. Christine Gleason for the eighth edition in 2004. Drs. Avery, Taeusch, and Ballard retired from editing the book in 2009, and became “editors emeriti.” Dr. Sherin Devaskar joined Dr. Gleason as co-editor for the ninth edition, bringing a wonderfully fresh perspective, as well as new contributors to the book. For this, the tenth edition, Dr. Sandra “Sunny” Juul teamed with Dr. Gleason as co-editor—the first time that co-editors have been faculty at the same institution since the fifth edition was published in 1984.

What’s New and Improved About This Edition? We are thrilled that the book is now in full color–no need to flip back and forth from the chapter text to the color plates at the front of the book! Also new to this edition are several Key Points that contributors have added to the beginning of each chapter, providing readers with a quick summary of the most important content. The Expert Consult eBook version includes new features, such as ultrasound videos, and has been enhanced to make content more easily searchable, shareable (via a new Social Media feature), portable, and perpetual. The book continues to be thoroughly (and sometimes painfully) revised and updated by some of the best clinicians and investigators in their field—several of whom are new contributors to this edition. Some chapters required more extensive revision than others, particularly those that deal with areas in which we have benefitted from new knowledge and/or its application to new diagnostic and therapeutic practices. This is particularly true in areas such as neurology, hematology, global health and neonatal screening, and genomics. Several new chapters have been added that reflect the continued growth and development of our subspecialty. These include chapters on brain injury (both preterm and term), palliative care, gastroesophageal reflux, platelet disorders, transfusion therapy, neonatal hypertension, and the ear/hearing disorders. With the incredible breadth and depth of information immediately available to neonatal caregivers and educators on multiple online sites, what’s the value of a printed textbook? We, the coeditors of this tenth edition, believe that textbooks such as Diseases of the Newborn and all forms of integrative scholarship, will always be needed—by clinicians striving to provide state-of-the-art neonatal care, by educators striving to train the next generation of caregivers, and by investigators striving to advance neonatal research and xxi

xxii

Preface

scholarship. A textbook’s content is only as good as its contributors and this textbook, like the previous editions, has awesome contributors. They were chosen for their expertise and ability to integrate their knowledge into a comprehensive, readable, and useful chapter. They did this despite the demands of their day jobs in the hopes that their syntheses could, as Ethel Dunham wrote in the foreword to the first edition, “spread more widely what is already known … and make it possible to apply these facts.” Although the online versions of this and other textbooks enjoy increasingly popular use, in 2017—a full 57 years after the publication of the first edition of this book—we still find copies of this and other textbooks important to our subspecialty lying dog-eared, coffee-stained, annotated, and broken-spined in places where neonatal caregivers congregate. These places, these congregations of neonatal caregivers, are now present in nearly every country around the world. The tentacles of neonatal practice and education are spreading—ever deeper, ever wider—to improve the outcome of pregnancy worldwide. Textbooks connect us to the past, bring us up to date with the present, and prepare and excite us for the future. We will always need them, in one form or another, at our sites of practice. To that end, we have challenged ourselves to meet, and hopefully exceed, that need—for our field, for our colleagues, and for the babies.

Acknowledgments and Gratitude We wish to thank key staff at Elsevier—Dee Simpson, senior developmental editor, Kate Dimock, our original publishing director, Sarah Barth, our new senior content strategist, and Sharon Corell, senior project manager. Each demonstrated patience, guidance, and persistence; without them, we would still be hard at work, trying to make this book a reality! We also wish to thank our staff and colleagues at our academic institution, the University of Washington, especially our Department Chair, F. Bruder Stapleton, whose leadership and unwavering support have meant a great deal to us both. We are indebted to our contributors, who actually wrote the book and did so willingly, enthusiastically, and (for the most part) in a timely fashion—despite myriad other responsibilities in their lives. Finally, we are deeply grateful for the support of our families throughout the long, and often challenging, editorial process. Christine Gleason and Sandra Juul

Video Contents Part XV: Hematologic System and Disorders of Bilirubin Metabolism 79 Neonatal Bleeding and Thrombotic Disorders 79-1 A Model of Hemostasis Combining the Vascular, Platelet, and Plasma Phases 79-2 Fibrinolysis 79-3 Hemostatic Processes

xxvii

PA RT I   Overview

1 

Neonatal and Perinatal Epidemiology NIGEL PANETH AND TRACY THOMPSON

KEY POINTS • Population-level study of pregnancy and infancy has been an important component of the success of newborn care. • Disease, mortality, and later outcomes patterns are complex. Some factors (i.e., preterm birth and birthweight) are stable, while others (i.e., cesarean section and twinning rates) can undergo rapid change. • The success of newborn intensive care is well established and has substantially lowered mortality rates in a short period of time primarily because of the evidence-based nature of neonatal practice. • Survivors of neonatal intensive care face educational and rehabilitative needs. Recent interventions have reduced the burden of brain damage. • Sudden infant death syndrome (SIDS), through careful epidemiologic study and active discouragement of prone sleeping, has been reduced by 70% in the United States. • Observational research and randomized trials have led to increased folate intake and a substantial reduction in neural tube birth defects.

T

he period surrounding the time of birth, the perinatal period, is a critical episode in human development, rivaling only the period surrounding conception in its significance. This time period is when the infant makes the critical transition from its dependence upon maternal and placental support (oxidative, nutritional, and endocrinologic) and establishes independent life. That this transition is not always successful is signaled by a mortality risk in the neonatal period that is not exceeded until age 75–84 and risks for damage to organ systems, most notably the brain, that can be lifelong (Murphy et al., 2013). The developing human organism often does not manifest the immediate effects of even profound insults. Years must pass before the damage to higher cortical functions of insults and injuries occurring during the perinatal period can be reliably detected. Epidemiologic approaches to the perinatal period must therefore be bidirectional: looking backwards from birth to examine the underlying causes of adverse health conditions that arise or complicate the perinatal period and looking forward to later life to see how these conditions shape disorders of health in childhood and adulthood.

Health Disorders of Pregnancy and the Perinatal Period Key Population Mortality Rates Maternal and child health in the population has traditionally been assessed by monitoring the two key rates of maternal mortality and infant mortality (IM). Maternal mortality is defined by the World Health Organization (WHO) as the death of a woman during pregnancy or within 42 days of pregnancy, denominated either to live births or to all births (this must be specified) in the population being studied (WHO, 2010). Because pregnancy can contribute to deaths beyond 42 days, some have argued for examining all deaths within a year of a pregnancy but later deaths are not included in standard tabulations of maternal mortality (Hoyert, 2007). When the cause of death is attributed to a pregnancy-related condition, it is described as direct. When pregnancy has aggravated an underlying health disorder present before pregnancy, the death is termed an indirect maternal death. The WHO recommends that both direct and total (direct plus indirect) maternal mortality rates be provided. Deaths unrelated to pregnancy, but taking place in women within 42 days of pregnancy, are termed incidental maternal deaths and are not included in maternal mortality (Khlat, 2006). But even incidental deaths may bear a relation to pregnancy; homicide and suicide, for example, are more common during pregnancy and shortly thereafter and might not be entirely incidental to it (Shadigian and Bauer, 2005; Samandari et al., 2010). In most geographic entities, IM is defined as all deaths occurring from birth to 365 days of age in a calendar year divided by all live births in the same year. This approach makes for imprecision, as some deaths in the examined year occurred in the previous year’s birth cohort, and some births in the examined year will die as infants in the following year. In recent years, birth–death linkage has permitted vital registration areas in the United States to provide IM rates that avoid this imprecision. The standard IM rate reported by the National Center for Health Statistics (NCHS) links deaths for the index year to all births, including those taking place the previous year. This form of IM is termed period IM. An alternative procedure is to take births for the index year and link them to 1

2

PART I  Overview

infant deaths, including those taking place the following year. This is referred to as birth cohort IM and is not used for regular annual comparisons because it cannot be completed in as timely a fashion as period IM (Mathews, 2015). Infant deaths are often divided into deaths in the first 28 days of life (neonatal deaths) and deaths later in the first year (postneonatal deaths). Neonatal deaths, which are largely related to preterm birth and birth defects, tend to reflect the circumstances of pregnancy whereas postneonatal deaths, when high, are nearly all from infection, often in the setting of poor nutrition. Thus in underdeveloped countries, postneonatal deaths dominate; in industrialized countries, the reverse is true. In the United States, neonatal deaths have been more frequent than postneonatal deaths since 1921. In recent years, the ratio of neonatal to postneonatal deaths in the United States has consistently been about 2 : 1. Perinatal mortality is a term used for a rate that combines stillbirths and neonatal deaths in some fashion (Box 1.1) Stillbirth reporting prior to 28 weeks, even in the United States, where such stillbirths are required to be reported in every state, is probably incomplete. Nonetheless, stillbirths continue to be reported at a level not much lower than that of neonatal deaths, and our understanding of the causes of stillbirth remains very uncertain (Paneth, 2012; Lawn et al., 2016).

Sources of Information on Mortality–Vital Data All US mortality data depend upon the collection of information about all births and deaths. Routinely collected vital data are the

• BOX 1.1 

Glossary of Terms

Preterm birth – less than 37 weeks’ gestation • Very preterm – less than 32 weeks’ gestation • Extremely preterm – less than 28 weeks’ gestation Low birth weight – infant weighs less than 2500 g (5 lb 8 oz) at birth regardless of gestational age • Moderately low birth weight – an infant weighing at least 1500 g but less than 2500 g at birth regardless of gestational age • Very low birth weight – an infant weighing less than 1000 g (2 lb 3 oz) at birth regardless of gestational age Maternal mortality ratio – death of a woman during pregnancy or within 42 days of pregnancy compared with either live births or with all births in the population • Direct maternal mortality – a maternal death attributed to a pregnancy-related cause • Incidental maternal mortality – a maternal death occurring during the defined time period for maternal mortality but unrelated to pregnancy • Indirect maternal mortality – a maternal death caused by the pregnancy aggravating an underlying health disorder present before pregnancy Infant mortality rate – all deaths occurring from birth to 365 days of age in a calendar year divided by all live births in the same year Birth cohort infant mortality – births for the index year are linked to infant deaths including those taking place the following year Neonatal mortality – infant deaths within the first 28 days of life Perinatal mortality rate – number of stillbirths that occur after 22 weeks’ gestation and deaths in the first week of life per 1000 total births Period infant mortality – all infant deaths in a calendar year linked to births, including births that took place in the previous year Postneonatal mortality – infant deaths after the first 28 days of life but before the 366th day of life

nation’s key resource for monitoring progress in caring for mothers and children. Annual counts of births and deaths collected by the 52 vital registration areas of the United States (50 states, District of Columbia, and New York City) are assembled into national data sets by the NCHS. Unlike data collected in hospitals or clinics, or even from nationally representative surveys, birth and death certificates are required by law to be completed for each birth and death. Birth and death registration have been virtually 100% complete for all parts of the United States since the 1950s. The universality of this process renders many findings from vital data analyses stable and generalizable, although formatting changes in 2003, affecting both the death and birth certificates, have created some difficulties in interpretation. For example, since 2003 the US Standard certificate of death, which is recommended for adoption by US vital registration areas, has included a special requirement for identifying whether the decedent, if female, was pregnant or had been pregnant in the previous 42 days. This simple check box on the death certificate has been shown to increase the number of deaths recognized as maternal in states that have followed the 2003 model and incorporated questions about pregnancy in their death certificates (Mac et al., 2011). Fig. 1.1 illustrates the most recent (2003) nationally recommended standard for birth certificate data collection, which had been adopted for use by 33 states by 2010 (Curtin et al., 2013). The remaining states use birth certificates formatted according to the 1989 standard. While, as we discuss below, some items are collected differently on the two certificate templates, unlike maternal mortality, these changes do not affect the number of reported deaths. The limitations of vital data are well known. Causes of death are subject to certifier variability and perhaps more importantly to professional trends in diagnostic categorization. The accuracy of recording of conditions and measures on birth certificates is often uncertain and variable from state to state and from hospital to hospital. Yet the frequencies of births and deaths in sub-groups defined objectively and recorded consistently, such as birthweight and mode of delivery, are likely to be valid.

Time Trends in Mortality Rates of the Perinatal Period in the United States Maternal mortality and IM declined steadily through the 20th century. By 2000, neonatal mortality was 10% of its 1915 value, postneonatal mortality less than 7%, and maternal mortality less than 2%. The contribution to these changes of a variety of complex social factors, including improvements in income, housing, birth spacing, and nutrition, has been widely documented, as has the role of ecologic-level public health interventions that have produced cleaner food and water (Division of Reproductive Health, 1999). Public health action at the individual level, including targeted maternal and infant nutrition programs and immunization programs, has made a lesser but still notable contribution. Medical care per se was, until recently, less critically involved, with the exception of the decline in maternal mortality, which was very sensitive to the developments in blood banking and antibiotics that began in the 1930s. To this day hemorrhage and infection account for a large fraction of the world’s maternal deaths (Khan et al., 2006). A notable feature of the past half-century or so is the sharp decline in all three mortality rates beginning in the 1960s following a period of stagnation in the 1950s (Fig. 1.2) The decline began with maternal mortality, followed by postneonatal, and then

CHAPTER 1  Neonatal and Perinatal Epidemiology

MOTHER

29a. DATE OF FIRST PRENATAL CARE VISIT ______ /________/ __________ No Prenatal Care MM DD YYYY

30. TOTAL NUMBER OF PRENATAL VISITS FOR THIS PREGNANCY _________________________ (If none, enter A0".)

31. MOTHER’S HEIGHT _______ (feet/inches)

32. MOTHER’S PREPREGNANCY WEIGHT 33. MOTHER’S WEIGHT AT DELIVERY 34. DID MOTHER GET WIC FOOD FOR HERSELF _________ (pounds) _________ (pounds) Yes No DURING THIS PREGNANCY?

35. NUMBER OF PREVIOUS LIVE BIRTHS (Do not include this child)

36. NUMBER OF OTHER 38. PRINCIPAL SOURCE OF 37. CIGARETTE SMOKING BEFORE AND DURING PREGNANCY PREGNANCY OUTCOMES PAYMENT FOR THIS For each time period, enter either the number of cigarettes or the (spontaneous or induced DELIVERY number of packs of cigarettes smoked. IF NONE, ENTER A0". losses or ectopic pregnancies) Average number of cigarettes or packs of cigarettes smoked per day. Private Insurance 36a. Other Outcomes # of cigarettes # of packs Medicaid Three Months Before Pregnancy _________ OR ________ Number _____ Self-pay _________ OR ________ First Three Months of Pregnancy Other Second Three Months of Pregnancy _________ OR ________ None (Specify) _______________ Third Trimester of Pregnancy _________ OR ________

35a. Now Living

35b. Now Dead

Number _____

Number _____

None

None

35c. DATE OF LAST LIVE BIRTH _______/________ MM YYYY

MEDICAL AND HEALTH INFORMATION

29b. DATE OF LAST PRENATAL CARE VISIT ______ /________/ __________ MM DD YYYY

36b. DATE OF LAST OTHER PREGNANCY OUTCOME _______/________ MM YYYY

41. RISK FACTORS IN THIS PREGNANCY (Check all that apply) Diabetes Prepregnancy (Diagnosis prior to this pregnancy) Gestational (Diagnosis in this pregnancy)

43. OBSTETRIC PROCEDURES (Check all that apply)

A. Was delivery with forceps attempted but unsuccessful? Yes No B. Was delivery with vacuum extraction attempted but unsuccessful? Yes No

None of the above

Previous preterm birth

44. ONSET OF LABOR (Check all that apply)

Other previous poor pregnancy outcome (Includes perinatal death, small-for-gestational age/intrauterine growth restricted birth) Pregnancy resulted from infertility treatment-If yes, check all that apply: Fertility-enhancing drugs, Artificial insemination or Intrauterine insemination Assisted reproductive technology (e.g., in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT)) Mother had a previous cesarean delivery If yes, how many __________ None of the above 42. INFECTIONS PRESENT AND/OR TREATED DURING THIS PREGNANCY (Check all that apply)

40. MOTHER’S MEDICAL RECORD NUMBER

46. METHOD OF DELIVERY

Cervical cerclage Tocolysis External cephalic version: Successful Failed

Hypertension Prepregnancy (Chronic) Gestational (PIH, preeclampsia) Eclampsia

Gonorrhea Syphilis Chlamydia Hepatitis B Hepatitis C None of the above

39. DATE LAST NORMAL MENSES BEGAN ______ /________/ __________ MM DD YYYY

Premature Rupture of the Membranes (prolonged, ∃12 hrs.)

C. Fetal presentation at birth Cephalic Breech Other D. Final route and method of delivery (Check one) Vaginal/Spontaneous Vaginal/Forceps Vaginal/Vacuum Cesarean If cesarean, was a trial of labor attempted? Yes No

Precipitous Labor (38°C (100.4°F) Moderate/heavy meconium staining of the amniotic fluid Fetal intolerance of labor such that one or more of the following actions was taken: in-utero resuscitative measures, further fetal assessment, or operative delivery Epidural or spinal anesthesia during labor None of the above

47. MATERNAL MORBIDITY (Check all that apply) (Complications associated with labor and delivery) Maternal transfusion Third or fourth degree perineal laceration Ruptured uterus Unplanned hysterectomy Admission to intensive care unit Unplanned operating room procedure following delivery None of the above

NEWBORN INFORMATION

NEWBORN

48. NEWBORN MEDICAL RECORD NUMBER 49. BIRTHWEIGHT (grams preferred, specify unit) ______________________ 9 grams 9 lb/oz 50. OBSTETRIC ESTIMATE OF GESTATION:

Mother’s Medical Record No. ____________________

Mother’s Name ________________

_________________ (completed weeks)

51. APGAR SCORE: Score at 5 minutes:________________________ If 5 minute score is less than 6, Score at 10 minutes: _______________________ 52. PLURALITY - Single, Twin, Triplet, etc. (Specify)________________________ 53. IF NOT SINGLE BIRTH - Born First, Second, Third, etc. (Specify) ________________

54. ABNORMAL CONDITIONS OF THE NEWBORN (Check all that apply) Assisted ventilation required immediately following delivery Assisted ventilation required for more than six hours NICU admission Newborn given surfactant replacement therapy Antibiotics received by the newborn for suspected neonatal sepsis Seizure or serious neurologic dysfunction Significant birth injury (skeletal fracture(s), peripheral nerve injury, and/or soft tissue/solid organ hemorrhage which requires intervention)

55. CONGENITAL ANOMALIES OF THE NEWBORN (Check all that apply) Anencephaly Meningomyelocele/Spina bifida Cyanotic congenital heart disease Congenital diaphragmatic hernia Omphalocele Gastroschisis Limb reduction defect (excluding congenital amputation and dwarfing syndromes) Cleft Lip with or without Cleft Palate Cleft Palate alone Down Syndrome Karyotype confirmed Karyotype pending Suspected chromosomal disorder Karyotype confirmed Karyotype pending Hypospadias None of the anomalies listed above

9 None of the above

56. WAS INFANT TRANSFERRED WITHIN 24 HOURS OF DELIVERY? 9 Yes 9 No IF YES, NAME OF FACILITY INFANT TRANSFERRED TO:______________________________________________________

57. IS INFANT LIVING AT TIME OF REPORT? 58. IS THE INFANT BEING BREASTFED AT DISCHARGE? Yes No Infant transferred, status unknown Yes No

• Fig. 1.1  United States National Standard Birth Certificate 2003 Revision.

3

PART I  Overview

4

US MATERNAL DEATH RATE

45

As reported by NCHS As reported by pregnancy mortality surveillance system

40 35

Rates

30 25 20 15 10 5 1956 1959 1962 1965 1968 1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 2010 2013

0

A

Years NEONATAL DEATH RATE

25

Neonatal death rate

Rates

20 15 10 5

1956 1959 1962 1965 1968 1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 2010 2013

0

B

Years POSTNEONATAL DEATH RATE

8

Postneonatal death rate

7 6

Rates

5 4 3 2 1 1956 1959 1962 1965 1968 1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 2010 2013

0

C • Fig. 1.2  Maternal,

Years

Neonatal, and Postneonatal Mortality Rates 1956– 2013. (A) United States maternal death rate. (B) Neonatal death rate. (C) Postneonatal death rate. NCHS, National Center for Health Statistics; US, United States. (From the pregnancy surveillance system https://www. cdc.gov/reproductivehealth/maternalinfanthealth/pmss.html and Martin JA, Hamilton BE, Ventura SJ, et al. Births: Final data for 2010. National vital statistics reports; vol 61 no 1. Hyattsville, MD: National Center for Health Statistics. 2012.)

neonatal. The contribution of medical care of the neonate was most clearly seen in national statistics in the 1970s, a decade that witnessed a larger decline in neonatal mortality than in any previous decade of the century. All of the change in neonatal mortality between 1950 and 1975 was in mortality for a given birthweight; no improvement was seen in the birthweight distribution (Lee et al., 1980). This finding suggested that the effectiveness of newborn intensive care has had a striking impact on mortality in very small babies. Prior to the development of newborn intensive care, survival at birthweights less than 1000 g was very rare. In 2013, the US survival rate to 1 year for infants with a birthweight between 501 and 999 g was 75%, and the number of survivors at age 1 was over 16,000. In retrospect, three factors seem to have played critical roles in the rapid development of the newborn intensive care programs that largely accounted for the rapid decline in birthweight-specific neonatal mortality that characterized national trends in the last third of the 20th century. The first was the willingness of medicine to provide more than nursing care to marginal populations such as the premature infant. While the death of the mildly premature son of President Kennedy in 1963 provided a stimulus to the development of newborn intensive care, it should be noted that the decline in IM that began in the 1970s was paralleled by a similar decline in mortality for the extremely old (Rosenwaike et al., 1980). This was, perhaps, an indicator that the availability of federal funding through Medicare and Medicaid enabled previously underserved populations at the extremes of age to receive greater medical attention than they had before. The Medicaid program, adopted in 1965, may have made it feasible for the first time to pay for the intensive care of premature newborns, among whom the medically indigent are over-represented. While financial support for newborn intensive care may have been a necessary ingredient in its development, finances would have not been sufficient to improve neonatal mortality had not new medical technologies, especially those supporting ventilation of the immature newborn lung, been developed at about the same time (Gregory et al., 1975). Advances in newborn care have ameliorated the impact of premature birth and birth defects on mortality. Unfortunately, the underlying disorders that drive perinatal mortality and the long-term developmental disorders that are sometimes their sequelae have shown no tendency to abate. With the very important exception of neural tube defects, whose prevalence has declined with folate fortification of flour in the United States and programs to encourage intake of folate in women of child-bearing age (Mathews et al., 2002), the major causes of death (preterm birth and birth defects) have not declined, nor has cerebral palsy, the major neurodevelopmental disorder that can be of perinatal origin (Paneth et al., 2006). Progress has come from improved medical care of the high-risk pregnancy and the sick infant, rather than through understanding and prevention of the disorders themselves. The pace of decline in infant, neonatal, and postneonatal mortality in the United States began to slow in 1995 and changed little in the following decade. A modest decline was seen, however, between 2005 and 2010 (Table 1.1). Data from the Vermont Oxford Neonatal Network encompassing more than a quarter of a million newborns from hundreds of largely North American neonatal units showed a decline in mortality of 12.2% for infants of 501–1500 g for 1990–1999 (Horbar et al., 2002) and a further 13.3% decline for 2000–2009 (Horbar et al., 2012). These declines are more modest than in the early days of newborn intensive care. From 1960–1985, a greater than 50% decline in mortality for

CHAPTER 1  Neonatal and Perinatal Epidemiology

TABLE 1.1 

5

United States Perinatal Mortality, Morbidity, Interventions, and Pregnancy Health Conditions and Behaviors, 1990–2005 1995

2000

2005

2010

Net Change 1995–2010 (%)

12.9

13.2

15.2

17.8

+ 38.0

Infant mortality rate

7.6

6.9

6.9

6.1

– 19.7

Neonatal mortality rate

4.9

4.6

4.5

4.0

– 18.4

Postneonatal mortality rate

2.6

2.3

2.3

2.1

– 19.2

6.9

6.6

6.2

6.0

– 13.0

11.0

11.6

12.7

12.0

+ 9.0

Very preterm birth (160/110 mmHg). Its role as an oral agent in the management of chronic hypertension is limited to a second or third-line choice. Long-term use of hydralazine may be associated with a lupus-like syndrome in some patients. Although diuretics are used extensively in nonpregnant adults with hypertension, there is little role for their use in women with chronic hypertension in pregnancy. Diuretics can potentially reduce or prevent the plasma volume expansion seen in normal pregnancy (Sibai et al., 1984), an effect that might impede fetal growth, although the evidence for this is mixed. Most authorities restrict the use of diuretics in pregnant patients to those with cardiac dysfunction or pulmonary edema. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should not be used during pregnancy. In the second and third trimesters, these agents are associated with malformation of the fetal calvarium, fetal renal failure, oligohydramnios, pulmonary hypoplasia, and fetal and neonatal death (Buttar, 1997). Angiotensin-converting enzyme inhibitors appear to be safe when taken in the first trimester (Steffensen et al., 1998), but a patient who conceives while taking an angiotensin receptor blocker or angiotensin-converting enzyme inhibitor should be switched to a safer alternative as soon as possible. Similar precautions apply to the use of angiotensin receptor blockers in pregnancy.

Antenatal Fetal Surveillance in Chronic Hypertension As women with chronic hypertension are at increased risk of slowing of fetal growth and of superimposed PE, antenatal surveillance in women with chronic hypertension should include careful screening for signs of superimposed PE and serial ultrasonographic evaluations every 3–6 weeks. All patients should perform fetal movement counts from 28 weeks’ gestation onward, and cases with slowing of fetal growth should be followed with twice-weekly nonstress tests with amniotic fluid index or a weekly ultrasound biophysical profile.

• BOX 12.1

121

Management of Pregnant Women With Chronic Hypertension

Monitoring • Daily home BP monitoring • Fetal growth sonography every 4 weeks • Fetal biophysical testing at least weekly from 32–34 weeks

Avoid • Low sodium diets • Weight loss prescriptions • Limitations of moderate exercise

Prophylaxis If prior pregnancy had PE with severe features and delivery was 160 mmHg and/or diastolic BP >110 mmHg, administer antihypertensive medication.

Prevention of Recurrent Preeclampsia If prior PE and delivery occurred prior to 34 0/7 weeks, begin daily low-dose aspirin (81 mg) prior to 15 weeks. BP, Blood pressure; PE, preeclampsia. Data from American College of Obstetricians and Gynecologists. Hypertension in Pregnancy. Washington, DC. American College of Obstetricians and Gynecologists; 2013.

TABLE 12.3 

Risk Factors for Development of Preeclampsia

Factor

Relative Risk

Primigravida

3

Age >40 years

3

African-American race

1.5

Family history

5

Chronic hypertension

10

Chronic renal disease

20

Antiphospholipid syndrome

10

Insulin-dependent diabetes mellitus

2

Multiple gestation

4

CHAPTER 12  Hypertensive Complications of Pregnancy 

hypertension, proteinuria secondary to glomerular injury, edema, and a tendency toward extravascular fluid overload with intravascular hemoconcentration.

Prediction Perhaps one of the most important contributions that prenatal care makes to maternal and fetal outcomes is the detection of PE and the prevention of eclampsia (Karbhari et al., 1972; Backe and Nakling, 1993). A wide variety of biochemical and physical tests have been proposed as screening tools for early detection of PE (Dekker and Sibai, 1991), but even the most widely used biochemical tests have poor predictive values. Uric acid levels are elevated in many cases of PE, but the sensitivity of the measurement is low (Lim et al., 1998). Clinicians should be aware of the limitations of routine urine testing for detection of proteinuria, with standard dipstick testing being notoriously inaccurate (Bell et al., 1999). Doppler ultrasonographic assessment of the vascular dynamics in the uterine arteries during the second trimester has been proposed as a screening tool in populations in which obstetric ultrasonography is routine (Cnossen et al., 2008). Up to 40% of women who develop PE have abnormal waveforms, and this finding was reported to be associated with a sixfold rise in the risk of PE (Papageorghiou et al., 2002). As no randomized trials to date have demonstrated convincingly the ability of uterine artery Doppler studies to predict PE, its use is currently not recommended (ACOG, 2013). The role of angiogenic factors in the pathophysiology of PE has become increasingly clear. Vascular endothelial growth factor (VEGF) and placental growth factor (PIGF), which bind to fms-like tyrosine kinase-1 (Flt-1) and soluble fms-like tyrosine kinase-1 (sFlt-1) receptors, have a critical role in angiogenesis and placental development. Flt-1, VEGF, and PIGF factor promote angiogenesis and placental vasculogenesis, whereas sFlt-1, VEGF, and PIGF inactivate those proteins, resulting in disordered angiogenesis and endothelial dysfunction. Levels of sFlt-1 are elevated in women with PE, and these elevated levels of sFlt-1 precede the features of clinical PE. Zeisler et al. (2016) recently reported a multicenter, prospective study of the ratio of sFlt-1 to PlGF in women between 24 weeks’ and 37 weeks’ gestation who presented with a clinical suspicion of PE or the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). An sFlt-1:PlGF ratio of 38 was the optimal cutoff in distinguishing between women in whom PE would develop and those in whom it would not develop in the next week. In a validation cohort of 550 women, a ratio of 0.38 or lower had a negative predictive value of 99.3% (95% confidence interval [CI], 97.9– 99.9). Despite the clear negative predictive value of an sFlt-1:PlGF ratio of less than 38 for PE diagnosis in the subsequent week, the clinical utility of this fact in managing pregnant women remains unclear. Thus at present, serum screening for PE risk is not recommended.

Prevention If an accurate predictor of PE could be identified, the next logical step would be the application of a preventive or ameliorative treatment. Unfortunately, attempts to identify an effective treatment have proved equally difficult. Given the recognized association between vascular endothelial dysfunction and PE, prostaglandin inhibitors have been proposed as a candidate for prophylaxis or treatment. Numerous trials (Duley et al., 2001) have been conducted

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with low-dose aspirin, based on the idea that the ability of aspirin to irreversibly inhibit production of the vasoconstrictive prostaglandin thromboxane would promote greater activity of prostacyclin, a vasodilatory prostaglandin. This ability of aspirin would help to maintain patency in the maternal placental vascular bed and limit or prevent the evolution of PE. In a recent systematic review of 34 randomized controlled trials (Bujold et al., 2010) of women at risk for recurrent PE, low-dose aspirin started at 16 weeks or earlier was associated with a significant reduction in PE (9.3% treated vs 21.3% control) and IUGR (7% treated vs 16.3% control), whereas aspirin started after 16 weeks was not. Low-dose aspirin started at 16 weeks or earlier also was associated with a reduction in severe PE (0.7% treated vs 15.0% control) and preterm birth (3.5% treated vs 16.9% control). Of note, all studies for which aspirin had been started at 16 weeks or earlier included women identified to be at moderate or high risk for PE. Calcium supplementation has been proposed as a preventive treatment on the basis of the known vasodilatory effect of calcium and impressive results in earlier, small studies (Atallah et al., 2000). Similarly, it has been suggested that antioxidants may have a role in PE prevention, but the only available trial to date showed mixed results, with improvements in biochemical indices in women receiving vitamins C and E, although perinatal outcomes were not different in treated and untreated groups (Chappell et al., 1999). Of concern was the finding that women in whom PE developed despite vitamin therapy had markedly worsened PE than controls in whom the disease developed. Two Cochrane systematic reviews (Hofmeyr et al., 2010, 2014) found that daily calcium supplementation significantly reduced the risk of PE and hypertension with and without proteinuria. However, women who received calcium supplements had a significantly higher risk of developing HELLP syndrome. Calcium supplementation had no effects on the risk of developing eclampsia, maternal death, or maternal admission to the intensive care unit. There was no effect of calcium supplementation on preterm birth, although a subgroup analysis suggested that there were fewer preterm births among women who received between 1.5 g and 2 g of elemental calcium per day. There was no effect on low birth weight, admission to a neonatal intensive care unit, stillbirth, and neonatal death. Thus in populations with low calcium intake, calcium supplementation is a reasonable intervention of uncertain net benefit.

Antepartum Management Given the current inability to predict or prevent PE in the majority of cases, clinicians should actively manage established disease and thus minimize maternal and fetal morbidity. The recognition that PE has a form with severe features is of great value in escalating management and minimizing morbidity (Box 12.3). Mild disease is generally managed expectantly with frequent fetal and maternal biophysical assessments until 37 weeks or there is evidence of severe features. The appearance of severe features mandates prompt delivery in all but highly selected cases regardless of gestational age. Patients with a diagnosis of PE should be regularly evaluated for severe features. This includes a 24-hour urine collection; complete blood count with platelet measurements; determination of serum uric acid, blood urea nitrogen, and creatinine levels; and evaluation of liver transaminases. Fetal size should be estimated with ultrasonography; the presence of IUGR (estimated fetal weight less

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• BOX 12.3  Preeclampsia and Severe Features Preeclampsia Diagnosis • Systolic blood pressure ≥140 mmHg or diastolic pressure of ≥90 mmHg twice at least 4 h apart • Proteinuria ≥300 mg/24 h (not required for diagnosis)

TABLE 12.4 

Drugs for Acute Treatment of Hypertension in Severe Preeclampsia

Drug

Dosage

Hydralazine

5 mg IV or IM, then 5–10 mg every 20–40 min as required, to a total of 30 mg or Constant intravenous infusion 0.5–10 mg/h

Labetalol

10–20 mg IV, then 20–80 mg every 20–30 min to a maximum of 300 mg or Constant intravenous infusion 1–2 mg/min

Nifedipine

10–20 mg PO, repeat in 30 min, then 10–20 mg every 2–6 h

Severe Features • Systolic blood pressure ≥160 mmHg or diastolic pressure of 110 mmHg on two occasions at least 4 hours apart while the patient is on bed rest • Pulmonary edema • HELLP syndrome: thrombocytopenia (platelet count 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease • Symptoms suggestive of end-organ involvement: headache, visual disturbance, epigastric, or right upper quadrant pain • Eclampsia From American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122:1122–1131.

than the 10th percentile), while no longer a criterion for severe PE, is a sign of jeopardy for the fetus. Patients with mild disease at 37 weeks’ gestation or more should be delivered, because prolonging pregnancy further increases the risks of maternal and fetal morbidity. Patients at earlier gestational ages should be closely monitored with sequential clinical and laboratory evaluations. Such monitoring often begins in the hospital and may be continued in an outpatient setting with appropriate supervision. Fetal well-being should be evaluated until delivery by means of kick counts and regular nonstress tests or modified biophysical profiles. There is no evidence that antihypertensive therapy influences progression of nonsevere PE, and it may actually be dangerous by masking worsening hypertension; therefore oral antihypertensive therapy should be avoided during expectant management. Conversely, severe hypertension requires prompt treatment with rapid-acting antihypertensive agents if stroke and placental abruption are to be avoided. Intravenous hydralazine is well established as a first-line drug for this purpose, although there is a growing experience with other agents, including intravenous labetalol and oral nifedipine (Duley and Henderson-Smart, 2000a) (Table 12.4). The aim of treatment is to lower blood pressure into the mild PE range (25 beats/min

Definition

Abrupt increase ≥15 beats/min lasting ≥15 s

Prolonged

≥2 min and 35 years) at the time of conception, with samples typically obtained by amniocentesis after 15 weeks’ gestation, or CVS at 10–12 weeks’ gestation. Maternal serum analyte testing is recommended for prenatal screening purposes for all pregnant women, with results showing low alpha fetoprotein, low unconjugated estriol, and elevated total human chorionic gonadotropin levels. Noninvasive prenatal screening is also accepted as an initial study for fetal aneuploidy (Committee Opinion 640, 2015). Associated ultrasonographic findings for Down syndrome, including a cardiac defect, shortened long bones, underdeveloped fetal nasal bone, nuchal translucency or thickening, echogenic small bowel, and duodenal atresia (“double-bubble” sign), may be seen in 50%–60% of fetuses. Most patients with Down syndrome, if it is not diagnosed prenatally, are usually recognized at birth because of the typical phenotypic features. The constellation of physical findings associated with Down syndrome consists of brachycephaly, the presence of a third or confluent fontanel, upward-slanted palpebral fissures, epicanthal folds, Brushfield spots in the irises, flattened nasal root, small posteriorly rotated ears with overfolded superior helices, prominent tongue, short neck with excess nuchal skin, single palmar creases, brachydactyly, fifth-finger clinodactyly, exaggerated gap between the first and second toes, open field hallucal pattern, and

• Fig. 20.2  Newborn with Down syndrome (trisomy 21) illustrating some of the characteristic facial features, including upward-slanting palpebral fissures and a flat facial profile.

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PART V  Genetics

hypotonia (see Fig. 20.2). Often the physical features conform to an easily distinguishable phenotype, but in some cases prematurity or ethnic variations can make a clinical diagnosis less straightforward. An immediate karyotype is indicated to confirm the diagnosis and its mechanism (e.g. trisomy, translocation) and as preparation for recurrence risk counseling for the family. Malformations involving many organ systems have been described in Down syndrome, and whether the diagnosis is known prenatally or determined in the newborn period, several clinical investigations are warranted when this diagnosis is suggested (Bull, 2011). The most common malformation is congenital heart disease (seen in approximately 50% of cases), which may require surgical intervention. Atrioventricular canal defects are often encountered (mean of 40%), although ventricular septal defects (VSDs), atrial septal defects (ASDs), tetralogy of Fallot, and patent ductus arteriosus (PDA) are all described in the disorder. An echocardiogram is indicated in all cases, and medical and surgical interventions for cardiac lesions are routine. Gastrointestinal malformations, especially duodenal atresia (2%–5%), in addition to Hirschsprung disease and less frequently encountered conditions, such as esophageal atresias, fistulas, and webs throughout the tract, have been described. It is critical to carefully monitor the baby’s feeding and bowel function before considering discharge from the nursery. Although growth parameters can be in the range of 10%–25% at birth, significantly decreased postnatal growth velocity is encountered in these patients. Separate growth curves have been devised for patients with Down syndrome (Fernandes et al., 2001), because growth retardation involving height, weight, and head circumference has been well documented. However, the most recent health supervision guidelines for patients with Down syndrome recommend that patients be assessed on the basis of the World Health Organization or Centers for Disease Control and Prevention growth curves (Bull, 2011). An initial ophthalmologic evaluation is also indicated in the first few months of life and then annually, because strabismus, cataracts, myopia, and glaucoma have been shown to be more common in children with Down syndrome. In addition, hearing loss of heterogenous origin is present in approximately half of patients, with middle ear disease contributing to this problem. Spinal cord compression caused by atlantoaxial subluxation from ligamentous laxity and subsequent neurologic sequelae can be a complication of the disorder. Radiographs are obtained when there is concern for myopathic symptoms related to spinal cord compression (weakness, abnormal reflexes, incontinence, etc.). Physicians should be vigilant in evaluating the cervical spine, especially before administration of anesthesia. Other associated disorders that merit screening are hypothyroidism in approximately 5% of patients, often with the presence of thyroid autoantibodies. Initial evaluation occurs with newborn screening programs, followed by additional measurement of thyroid-stimulating hormone and free thyroxine levels at 6 months, 12 months, and then yearly thereafter. Bone marrow dyscrasias, such as neonatal thrombocytopenia, and transient self-resolving myeloproliferative disorders, such as leukemoid reaction, have been observed in the first year of life, and a complete blood count with differential should be performed at birth. An elevated rate of leukemia with a relative risk 10–18 times greater than normal up to age 16 years has been described. Acute nonlymphoblastic leukemia is seen at higher rates in congenital or newborn cases, but the distribution becomes similar to that of non–Down syndrome patients after age 3 years. Survival of patients with Down syndrome is shorter after a diagnosis of acute lymphoblastic leukemia than in diploid patients (Epstein,

2001). There is also an increased risk of iron-deficiency anemia, with recommended screening to include annual hemoglobin level measurement starting at 12 months of age then annually thereafter. If the hemoglobin level is low, then a complete blood count with iron studies should be performed. Patients with Down syndrome demonstrate a wide range of developmental abilities, with highly variable personalities and behavioral phenotypes as well (Pueschel et al., 1991). Central hypotonia with concomitant motor delay is most pronounced in the first 3 years of life, as are language delays. Therefore immediate and intensive early intervention and developmental therapy are critical for maximizing the developmental outcome. A wide range of intelligence has been described, with conflicting data on genetic and environmental modifiers of outcome (Epstein, 2001). Seizure disorders occur in 5%–10% of patients, often manifesting themselves in infancy. The most common causes of death in patients with Down syndrome are related to congenital heart disease, to infection (e.g., pneumonia) that is thought to be associated with defects in T-cell maturation and function, and to malignancy (Fong and Brodeur, 1987). Once medical and surgical interventions for the correction of associated congenital malformations are complete and successful, the long-term survival rate is good. However, less than half of patients survive to 60 years, and less than 15% survive past 68 years. Neurodegenerative disease with features of Alzheimer disease is encountered in most patients who are older than 40 years. The gene for amyloid precursor protein (APP) is on chromosome 21, and overexpression of this gene in the trisomic state leads to earlyonset beta-amyloid plaques in the brain. Neurofibrillary tangles, cerebrovascular pathology, white matter pathology, oxidative damage, neuroinflammation, and neuron loss are also seen in the brains of patients with Down syndrome. Frank dementia is not typical, as there appear to be compensatory responses that delay the onset of dementia after the development of amyloid deposition (Head et al., 2016). Men with Down syndrome are almost always infertile, whereas small numbers of affected women have reproduced (Epstein, 2001). In counseling the family of a newborn in whom Down syndrome has been diagnosed, it is important to include the organ systems affected in the baby and the severity of each malformation when one is defining a prognosis. Above all, the wide variability of the phenotype should be emphasized, with a care plan tailored to the needs of the individual patient.

Genetic Counseling If a complete (full chromosome) or mosaic trisomy 21 is found, parental karyotypes are generally not analyzed, because the karyotypes are normal in virtually all cases. After having one child with Down syndrome, a mother’s recurrence risk for another affected child is approximately 1% higher than her age-specific risk (Hook, 1992). This fact is especially significant in younger mothers, whose age-specific risks are low. If a de novo translocation resulting in Down syndrome is found, the recurrence risk is less than 1%. If the mother is found to carry a constitutional balanced Robertsonian translocation, the risk of another translocation Down syndrome fetus is approximately 15% at the gestational age when amniocentesis is offered and 10% at birth. However, if the father is the translocation carrier, the recurrence risk is significantly smaller, approximately 1%–2% (Epstein, 2001). Whereas array-based diagnostic techniques will identify the copy number change associated with the trisomy, structural rearrangements such as Robertsonian translocations are not readily detected. In this situation a karyotype will provide

CHAPTER 20  Chromosome Disorders

information regarding the mechanism of the copy number change, which is needed for accurate recurrence risk counseling.

Trisomy 18 (Edwards Syndrome) Trisomy 18 is encountered in 1 in 6000 live births and is associated with a high rate of intrauterine demise. It is estimated that only 5% of conceptuses with trisomy 18 survive to birth and that 30% of fetuses in whom trisomy 18 is diagnosed by second-trimester amniocentesis die before the end of the pregnancy (Hook, 1992). Findings on prenatal ultrasonography can raise suspicion for the disorder – growth retardation, oligohydramnios or polyhydramnios, heart defects, myelomeningocele, clenched fists, and limb anomalies. Diagnostic testing is recommended when prenatal ultrasonography findings are suggestive of this condition. Maternal serum screening can show low values for alpha fetoprotein, unconjugated estradiol, and total human chorionic gonadotropin.

Clinical Features Phenotypic features present at birth consist of intrauterine growth restriction (1500–2500 g at term), small narrow cranium with prominent occiput, open metopic suture, low-set posteriorly rotated ears, and micrognathia with small mouth. Characteristic clenched hands with overlapping digits, excess of arches on dermatoglyphic examination, hypoplastic nails, and “rocker-bottom” feet or prominent heels with convex soles (Fig. 20.3) are also described. Additional malformations encountered in this syndrome include congenital heart disease (ASD, VSD, PDA, pulmonic stenosis, aortic coarctation), cleft palate, clubfoot deformity, renal malformations, brain anomalies, choanal atresia, eye malformations, vertebral anomalies, hypospadias, cryptorchidism, and limb defects, especially of the radial rays. The prognosis in this disorder is extremely poor, with more than 90% of babies succumbing in the first 6 months of life and only 5% alive at 1 year old. Death is caused by central apnea, infection, and congestive heart failure. The newborn period is characterized by poor feeding and growth, typically requiring tube feedings. Universal poor growth and profound mental retardation

• Fig. 20.3  Newborn with trisomy 18, showing prominent occiput, characteristic facial appearance, and clenched hands.

215

with developmental progress typically leveling at that of a 6-monthold infant (Baty et al., 1994) have been documented. Malignant tumors such as hepatoblastoma and Wilms tumor have been described in some survivors. There is emerging evidence that various interventions can improve the survival and quality of life for the child and the family, and this should be discussed with the parents during a prenatal or postnatal visit (Carey, 2012; Kosho and Carey, 2016).

Genetic Counseling The typical estimate of the recurrence risk for trisomy 18 in a future pregnancy is a 1% risk over the maternal age–specific risk for any viable autosomal trisomy (Hook, 1992). Trisomy occurring from a structural rearrangement, such as a translocation, warrants parental karyotype analysis before the recurrence risk can be assessed.

Trisomy 13 (Patau Syndrome) It has been estimated that approximately 2%–3% of fetuses with trisomy 13 survive to birth, with a frequency of 1 in 12,500 to 1 in 21,000 live births (Hook, 1992). As with other trisomies, abnormal noninvasive prenatal screening findings for advanced maternal age or the presence of fetal ultrasonographic findings may prompt diagnostic testing by CVS or amniocentesis that can result in a prenatal diagnosis of trisomy 13.

Clinical Features Trisomy 13–associated midline malformations include congenital heart disease, cleft palate, holoprosencephaly, renal anomalies, and postaxial polydactyly (Fig. 20.4). In addition, microcephaly, eye

• Fig. 20.4 Stillborn

With Trisomy 13. The facial appearance is that of cebocephaly, which is associated with holoprosencephaly. There is an extra digit on the ulnar border of the right hand.

216

PART V  Genetics

anomalies, and scalp defects can suggest the diagnosis. Brain malformations such as holoprosencephaly are found in more than half of patients with concomitant seizure disorders. Microcephaly, split sutures, and open fontanels are encountered. A scalp defect (cutis aplasia) that has sometimes been mistakenly attributed to a fetal scalp monitor is specific to the disorder, being found in 50% of cases. Eye malformations, including iris colobomas and hamartomatous cartilage “islands,” can be seen on fundoscopic examination. Congenital heart disease is present in approximately 80% of patients, usually VSD, ASD, PDA, or dextrocardia. Limb anomalies, such as postaxial polydactyly, single palmar creases, and hyperconvex narrow fingernails, are also seen. The fingers can be flexed or overlapped and can show camptodactyly. An increased frequency of nuclear projections in neutrophils, giving a drumstick appearance similar to that of Barr bodies, can also be found. This finding would be especially striking in males, in whom Barr bodies would not be expected. As with trisomy 18, prognosis for the fetus with trisomy 13 is extremely poor, with 80% mortality in the neonatal period and less than 5% of patients surviving to 6 months old. Mental retardation is profound, and many patients are blind and deaf as well. Feeding difficulties are typical. Also similar to trisomy 18, various interventions can increase the survival of these infants and improve their overall quality of life. A discussion with the parents should be considered regarding these possibilities (Carey, 2012; Kosho and Carey, 2016).

Genetic Counseling Recurrence risk data suggest that, as with trisomy 18, the chance that a woman will have a child with any trisomy after a pregnancy affected by trisomy 13 is rare. The estimated risk is 1% higher than the maternal age–related risk for the recurrence of any viable autosomal trisomy in a subsequent pregnancy.

45,X (Turner Syndrome) In early embryogenesis, two active X chromosomes are required for normal development. Turner syndrome, a phenotype associated with loss of all or part of one copy of the X chromosome in a female conceptus, occurs in approximately 1 in 2500 female newborns. The 45,X karyotype or loss of one entire X chromosome accounts for approximately half of the cases. A variety of X chromosome anomalies—including deletions, isochromosomes, ring chromosomes, and translocations—account for the remainder of the causes. It is important to note that approximately 0.1% of fetuses with a 45,X complement survive to term; the vast majority (>99%) are spontaneously aborted. This fact underscores the requirement for both X chromosomes during embryonic development. Additional studies indicate that in approximately 80% of cases, it is the paternally derived X chromosome that is lost (Willard et al., 2001).

Clinical Features There is wide phenotypic variability in patients with Turner syndrome. Features present at birth include short stature, webbed neck, craniofacial differences (epicanthal folds and high arched palate), hearing loss, shield chest, renal anomalies, lymphedema of the hands and feet with nail hypoplasia, and congenital heart disease. Typical cardiac defects include bicuspid aortic valve, coarctation of the aorta, valvular aortic stenosis, and mitral valve prolapse.

Growth issues, especially short stature, are the predominant concern in childhood and adolescence; the mean adult height of patients with Turner syndrome is 135–150 cm without treatment. Growth hormone therapy has been shown to increase final adult height, with the age of initiation of therapy not yet established, but it can be administered as early as 9 months (Bondy, 2007). Primary ovarian failure caused by gonadal dysplasia (streak gonads) can result in delay of secondary sexual characteristics and primary amenorrhea. Cyclic hormonal therapy should reflect the process of normal puberty (Bondy, 2007) to aid the development of secondary sex characteristics and menses as well as to help bone mass. Infertility, related to gonadal dysplasia, is typical and has been successfully treated with assisted reproduction techniques and donor oocytes. It is important to evaluate the patient for structural cardiovascular defects before pregnancy. In terms of intellectual development, specific difficulties with spatial and perceptual thinking lead to a lower performance intelligence quotient; however, this syndrome is not characterized by mental retardation.

Triploidy (69,XXX or 69,XXY) As its name implies, triploidy is a karyotype containing three copies of each chromosome. The mechanisms that lead to this state include fertilization of the egg by two different sperm (dispermy) and complete failure of normal chromosome separation in maternal meiosis. The vast majority of triploid fetuses are spontaneously aborted, accounting for up to 15% of chromosomally abnormal pregnancy losses. Live births of affected fetuses are rare, and reports of survival beyond infancy are only anecdotal. Mosaicism with combinations of diploid and triploid cells (mixoploid) has also been documented. Malformations, including hydrocephalus, neural tube defects, ocular and auricular malformations, cardiac defects, and 3–4 syndactyly of the fingers, are associated findings. In addition, the placenta is often abnormal, typically large, and cystic.

Deletion Syndromes In addition to the aneuploid conditions described previously, partial monosomy of a chromosome can lead to a recognizable pattern of malformation. Three well-described syndromes that are associated with the deletion or loss of genetic material from the short, or p, arms of chromosomes 1, 4, and 5 are described. All these syndromes are associated with heterozygous deletions that involve the loss of many genes located in a specific region, or haploinsuffiency.

Chromosome 1p Deletion Syndrome (1p–) Monosomy for the distal short arm of chromosome 1, or deletion of 1p36, has been associated with a constellation of clinical findings. A characteristic facies consisting of frontal bossing, large anterior fontanel, flattened midface with deep-set eyes, and developmental delay has been described (Fig. 20.5). Orofacial clefting, hypotonia, seizures, deafness, and cardiomyopathy are also noted. This deletion syndrome is estimated to occur in approximately 1 in 10,000 live births, and it is the most frequently occurring subtelomeric deletion. Greater recognition of the phenotype and widespread use of chromosomal microarrays has led to improved diagnosis of this condition. Most deletions arise de novo in the patient, with approximately 3% being attributable to malsegregation of a balanced parental translocation. The size of the deletion differs, from submicroscopic (T and c.625G>A) with the biochemical abnormalities of SCADD (Pedersen et al., 2008). Currently, most infants with SCADD are detected on NBS and remain clinically asymptomatic leading many to consider this a benign condition (Gallant et al., 2012). The need for treatment, carnitine or riboflavin supplementation, or management during illness is unclear (Wolfe et al., 1993).

Very Long Chain Acyl-CoA Dehydrogenase Deficiency

The mitochondrial trifunctional protein complex of four alpha and four beta subunits comprises three enzymes: long-chain enoylCoA hydratase, long-chain 3-hydroxy acyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase. Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency (LCHADD) occurs when there is only reduced dehydrogenase activity because of mutations in the HADHA gene, while trifunctional protein deficiency (TFP) results from mutations in either the HADHA or HADHB gene and in deficient activity of all three enzymes. The prevalence of LCHADD is approximately 1 in 110,000 while TFP is much rarer (Das et al., 2006). The most severe forms of LCHADD or TFP present with a rapidly progressive neonatal cardiomyopathy (Spiekerkoetter et al., 2009a; Sperk et al., 2010). Infants may later develop recurrent hypoketotic hypoglycemia with acute catabolic illness resulting in liver dysfunction (a Reye-like syndrome), cardiomyopathy, myopathy, and rhabdomyolysis. Sixty-five percent of surviving individuals with LCHADD or TFP experience skeletal myopathy, 21% develop a slowly progressing peripheral neuropathy, and 43% have pigmentary retinopathy (Spiekerkoetter et al., 2009a). Some patients may have severe liver disease with fibrosis in addition to necrosis and steatosis. Older children, adolescents, and adults may develop recurrent rhabdomyolysis during illness. Heterozygous mothers may rarely develop either acute fatty liver of pregnancy or hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) when carrying a child with LCHADD (Ibdah et al., 1999). Diagnosis is made through the demonstration of elevations of C16:1-OH-, C16-OH-, C18:1-OH-, and C18-OH-acylcarnitines levels and the demonstration of longer-chain 3-hydroxydicarboxylic acids on urine organic acid analysis. Enzymatic diagnosis can be made in lymphocytes or in skin fibroblasts, but a combination of clinical biochemical abnormalities and HADHA or HADHB mutation analysis is often sufficient. The majority of moderateto-severe cases are diagnosed by NBS. Follow-up of cases diagnosed on NBS demonstrates improved growth and development, but NBS does not completely prevent morbidity and mortality, especially in TFP, which has poorer survival (Sander et al., 2005; Spiekerkoetter et al., 2009a; Sperk et al., 2010; Wilcken, 2010). Treatment of LCHADD and TFP involves avoidance of prolonged fasting, dietary fat restriction, and MCT supplementation. A low-fat diet and MCT supplementation decrease plasma hydroxyl acylcarnitine levels, and most LCHADD patients remain healthy without metabolic decompensation but still require supplementation with essential fatty acids and fat-soluble vitamins (Gillingham et al., 2003).

VLCADD has been estimated to affect between 1 in 100,000 to 1 in 120,000 individuals, but prevalence may be as high as 1 in 42,500 (Zytkovicz et al., 2001; Chace et al., 2002; Spiekerkoetter et al., 2003; Wilcken et al., 2003). VLCADD presents with variable phenotypes ranging from severe cardiomyopathy that may result in death in the first few days of life to recurrent hypoketotic hypoglycemia or to later-onset presentations with myopathy and/ or rhabdomyolysis in adolescence or adulthood (Bertrand et al., 1993; Bonnet et al., 1998; de Lonlay-Debeney et al., 1998; Bonnet et al., 1999; Kluge et al., 2003; Hoffman et al., 2006). Cardiomyopathy and arrhythmias have been reported in a high proportion of cases presenting at less than 6 years in a country without newborn screening (Baruteau et al., 2014). Most patients with VLCADD are detected through NBS but present a significant challenge in that a large number of individuals appear to have mild or perhaps benign DNA variants and normal follow-up plasma acylcarnitine profiles. Many of these cases will have a single heterozygous mutation and so appear to be unaffected carriers. Others may have two compound heterozygous mutations but have a reduced clinical risk of symptoms. Plasma acylcarnitines show a pattern of elevations of C14:1-, C14-, C16:1-, and C16-acylcarnitines levels with low secondary free carnitine levels in some infants. With an acute metabolic decompensation, urine organic acid analysis may demonstrate dicarboxylic aciduria. Confirmation by sequencing and deletion/duplication analysis of ACADVL is recommended. Functional enzyme assay or fibroblast acylcarnitine probe analysis may be helpful to determine treatment when a single heterozygous mutation is found, novel uncharacterized variants are found, and/or there are persistent elevations of acylcarnitines inconsistent with the genotype (Pena et al., 2016). Treatment follows the general principles for long-chain FAOD treatment, consisting of fasting avoidance, dietary fat restriction, MCT supplementation, and carnitine supplementation if necessary. Infants should discontinue breastfeeding because of the high fat content in breast milk, with implementation of an MCT-containing formula (Spiekerkoetter et al., 2009b). Treatment of milder forms of VLCADD may include supplementation of breastfeeding with an MCT-containing formula.

Short-Chain Acyl-CoA Dehydrogenase Deficiency Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is diagnosed through the detection of elevations of C4-acylcarnitine, urinary ethylmalonic acid, and butyrylglycine. Prior reports found decreased SCAD enzyme activity to be associated with failure to thrive, poor feeding, hypotonia, and seizures. Subsequently, up to 14% of the

Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency and Trifunctional Protein Deficiency

Primary Carnitine Transporter Deficiency Carnitine is essential for long-chain fatty acid transport across the mitochondrial inner membrane. This is dependent upon a

CHAPTER 22  Inborn Errors of Carbohydrate, Ammonia, Amino Acid, and Organic Acid Metabolism 

sodium-dependent carnitine transporter, two transferases that covalently link and then remove carnitine to the long-chain fatty acid, and a translocase. Carnitine transporter deficiency (CTD, primary carnitine deficiency, carnitine uptake defect) is characterized by hypoketotic hypoglycemia, hyperammonemia, liver dysfunction, cardiomyopathy, and skeletal hypotonia. Neonatal presentations are not common. In some older patients, cardiomyopathy may be the presenting sign. Profoundly low plasma total and free carnitine levels (typically T (p.P479L), has been identified in the Arctic populations of the Inuit, Alaskan Native, Canadian First Nation, and Hutterite and has been associated with higher infant mortality and impaired fasting intolerance in these populations (Collins et al., 2010; Gillingham et al., 2011; Clemente et al., 2014). Treatment involves fasting avoidance, low-fat diet, and MCT supplementation and results in a normal outcome, although some suffer neurologic impairment from repeated episodes of metabolic decompensation (Bonnefont et al., 2004; Longo et al., 2006).

Carnitine Acylcarnitine Translocase Deficiency CACT is one of the more severe FAODs, and the most common presentation is ventricular dysrhythmia and sudden neonatal death (Yang et al., 2001; Wilcken, 2010). Symptoms include hypoglycemia, vomiting, gastroesophageal reflux, and mild chronic hyperammonemia, as well as severe skeletal myopathy and mild hypertrophic cardiomyopathy. Early diagnosis and treatment can be beneficial, although significant morbidity includes profound developmental delay, seizures, and other complications despite NBS (Pierre et al., 2007; Al-Sannaa and Cheriyan, 2010; Spiekerkoetter, 2010; Wilcken, 2010). Milder disease is associated with higher residual enzyme activity (Rubio-Gozalbo et al., 2004).

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Individuals will have elevated C16-, C16:1-, C18-, and C18:1acyclarnitine levels with low free carnitine levels on diagnostic testing and NBS. DNA sequencing of SLC25A20 will confirm disease. Treatment includes fasting avoidance with a low- fat, high-carbohydrate formula, MCT supplementation, and carnitine.

Carnitine Palmitoyltransferase Type II Deficiency Carnitine palmitoyltransferase type II deficiency (CPTII) results in elevations of C16- and C18:1-acylcarnitines in NBS as found with CACT deficiency; DNA testing is required for diagnosis; treatment depends on severity. Children with the severe form of CPTII deficiency may have congenital anomalies including renal cysts, dysmorphic facies, and brain malformations and may present with hypotonia, cardiomyopathy, arrhythmias, and seizures within the newborn period (Albers et al., 2001). The later-onset form of CPTII deficiency is much more common and presents in the second or third decade of life with exercise intolerance or rhabdomyolysis (Longo et al., 2006). Confirmatory sequencing of the gene CPT2 will reveal mutations (Wieser et al., 2003).

Multiple Acyl-CoA Dehydrogenase Deficiency Multiple acyl-CoA dehydrogenase deficiency (MADD; also called glutaric acidemia type 2) is the result of a defect of electron transfer from multiple acyl-CoA dehydrogenases to the mitochondrial ETC. Each acyl-CoA dehydrogenase enzyme binds electron transfer flavoprotein (ETF). ETF accepts electrons from the FADH2 cofactor in the oxidative dehydrogenation reactions and is made up of three subunits. Mutations in the genes for the three subunits, ETFA, ETFB, and ETFDH, will interfere with electron transfer from ETF to coenzyme Q10 within the mitochondria. Riboflavin (an FADH2 component) deficiency or deficient riboflavin transport may show a similar presentation—a riboflavin-responsive form of MADD has been described. Because of the multiple dehydrogenase enzymes involved there will be elevations of metabolites from short-, medium-, and long-chain fatty acids and amino acid metabolism. MADD may present in three major ways. The first two present in the newborn period, with or without congenital anomalies, and the third is a later-onset type. Neonatal MADD presents with metabolic acidosis, hypoketotic hypoglycemia, and often hypertrophic cardiomyopathy. Those with congenital malformations may have enlarged polycystic kidneys, rocker-bottom feet, defects of the inferior abdominal musculature, and hypospadia and chordee. Hypotonia, cerebral cortical dysplasia, and gliosis have been reported, and dysmorphic facies may include telecanthus, malformed ears, macrocephaly, large anterior fontanel, high forehead, and a flat nasal bridge (Wilson et al., 1989). Older patients with the later-onset MADD do not have congenital malformations but have a lifelong risk of acute intermittent episodes with vomiting, dehydration, hypoketotic hypoglycemia, and acidosis. In some there may be hepatomegaly and muscle disease. Many infants do not survive beyond the first few weeks or months of life because of rapidly progressing cardiomyopathy. In individuals identified through NBS and in whom treatment is initiated early, acute, life-threatening events or sudden death may still occur (Angle and Burton, 2008; Singla et al., 2008). Diagnosis of MADD is suspected due to the combination of increased anion gap lactic acidosis, hypoketotic hypoglycemia, and hyperammonemia. They may have an odor of isovaleric acid. Increased serum transaminases and prolongations of prothrombin

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time and partial thromboplastin time suggest liver dysfunction. Diagnostic testing should include plasma acylcarnitines with elevations of C4 and C5 acylcarnitines (which are the primary analytes on NBS), but medium- and long-chain acylcarnitines may also be present (i.e., C8-, C10:1-, C12-, C14-, C14:1-, C16-, C16:1-, C18-, C18:1-, C16-OH-, C16:1-OH-, C18-OH-, and C18:1-OH-acylcarnitines). Urine organic acid analysis will show elevations of ethylmalonic acid, glutaric acid, and 3-hydroxyisovalerate in addition to lactic acid, medium- and long-chain dicarboxylic acids, the glycine conjugates isovalerylglycine, isobutyrylglycine, and 2-methylbutyrylglycine. Ketone bodies, including acetoacetic acid and 3-hydroxybutyric acids, are minimal or undetectable. Generalized aminoaciduria will reflect impaired renal tubular function. DNA sequencing of ETFA, ETFB, and ETFDH will confirm the diagnosis. Treatment of MADD includes a low-protein and low-fat diet, fasting avoidance, and supplementation with carnitine, riboflavin, and glycine. Individualized metabolic formulas often have to be designed to meet nutritional goals. Individuals at least heterozygous for common ETFDH mutations confer a milder riboflavin-responsive phenotype with some cases of complete correction of clinical and biochemical parameters after riboflavin treatment (Olsen et al., 2007). Acute decompensation should be treated with IV glucose and carnitine to restore anabolism with close monitoring of cardiac, hepatic, and renal function.

Ketone Metabolism Disorders Disorders of ketone metabolism result from the inability to use ketone bodies, 3-hydroxybutyric acid and acetoacetic acid, for energy generation. Each cycle of the fatty acid β-oxidation generates a single acetyl-CoA. This acetyl-CoA has to be converted to acetoacetic acid by mitochondrial acetoacetyl-CoA thiolase, 3-hydroxy3-methylglutaryl CoA (HMG-CoA) synthase, and then HMG-CoA lyase. Acetoacetic acid and 3-hydroxybutyric acid are transported out of liver mitochondria and hepatocytes into blood to be used by other tissues, especially the brain and heart. Patients with mitochondrial acetoacetyl-CoA thiolase deficiency (β-ketothiolase or 3-oxothiolase deficiency) have a metabolic acidosis associated with excess ketosis. Most commonly presenting in children around 15 months of age, cases are reported as early as 3 and 4 days of age with lethargy, metabolic ketoacidosis, and an elevated anion gap (Fukao et al., 2001; Cubillo Serna et al., 2007). The clinical presentation varies from severe, acute metabolic decompensation in infants to asymptomatic adults. The episodes are intermittent, are typically associated with a catabolic stressor or a high dietary protein intake, and have been associated with mild hyperketotic hypoglycemia and liver dysfunction, without hyperammonemia. Cardiomyopathy is rare. Plasma acylcarnitines and NBS will demonstrate elevations of C5-OH- and C5:1-acylcarnitines. Urine organic acid analysis demonstrates significant elevations of lactate and ketone bodies and a specific pattern of elevations of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine. Older children and adults have ketoacidosis while others have remained asymptomatic. Diagnosis is confirmed by DNA sequence analysis of the ACAT1 gene looking for mutations in this autosomal recessive disorder. Acute treatment involves IV glucose and bicarbonate to correct metabolic acidosis, which is often severe, while long-term therapy includes mild protein restriction, avoidance of fasting, and prompt attention to any intercurrent illness or catabolic stressor, as treatment and avoidance of severe ketoacidosis may lead to normal development.

The most severe disorder of ketone metabolism is the last step in synthesis of acetoacetate from HMG-CoA via the HMG-CoA lyase enzyme. Neonates present as early as 3 days of life with an often-catastrophic illness characterized by vomiting, lethargy, hypoketotic hypoglycemia, metabolic acidosis, hyperammonemia, elevated transaminases, hepatomegaly, seizures, and coma. Urine organic acid analysis reveals 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, and 3-hydroxyisovaleric acid in a specific diagnostic pattern with elevations of C5-OH- and C6-DC-acylcarnitines on plasma acylcarnitine analysis and NBS. Levels of acetoacetic acid and 3-hydroxybutyric acid may be unexpectedly low. Lactate values may be elevated during the acute metabolic decompensation. An autosomal recessive disorder, the HMG-CoA lyase deficiency is confirmed by mutation analysis of the HMGCL gene. Acute treatment of the episode consists of administration of IV rehydration and administration of glucose and bicarbonate, to correct metabolic acidosis. Long-term treatment consists of avoiding prolonged fasting, a low-protein and high-carbohydrate diet, and carnitine supplementation (Gibson et al., 1988). Succinyl-CoA 3-ketoacid-CoA transferase deficiency results from the failure of extrahepatic tissues to convert acetoacetate back to acetoacetyl-CoA. This is required for hydrolysis to acetyl-CoA for final metabolism in the TCA cycle. Affected patients have a persistent ketosis with intermittent ketoacidosis that does not resolve, even postprandially. Affected newborns often present in the 1st week of life with severe ketosis, lactic acidosis, hypoglycemia, and coma, and many do not survive (Fukao et al., 2014). Elevated acetoacetate and 3-hydroxybutyrate levels are almost always present in blood and urine. Therapy focuses on fasting avoidance, which can cause profound acidosis and ketosis, and IV fluids, glucose, and sodium bicarbonate during crisis. Enzyme analysis in fibroblasts is available, but DNA sequencing of the OXCT1 gene will confirm the diagnosis in this autosomal recessive disorder. Milder forms do exist, and patients may have nonketotic periods.

Primary Lactic Acidosis Congenital lactic acidosis (CLA) is due to a severe disorder of energy metabolism. This can be caused by one of multiple diseases, including those in which lactate and pyruvate metabolism are impaired because of a primary defect in the mitochondrial ETC or the tricarboxylic acid (TCA) cycle. These disorders affect pyruvate metabolism, which, in turn, affects lactate. The majority of neonates presenting with CLA have defects of the mitochondrial ETC or the PDH complex or PC deficiency. Inborn errors of the TCA cycle are much rarer but should be considered in the differential diagnosis. A recently described autosomal recessive disorder of metabolism of the amino acid valine, short-chain enoyl-CoA hydratase deficiency because of mutations in the ECHS1 gene, appears to cause a secondary inhibition of PDH and can present with refractory CLA with a Leigh disease-like presentation, neurodegeneration, and neonatal death (Ferdinandusse et al., 2015). Some patients with CLA present with overwhelming lactic acidosis in the neonatal period. In others, lactate may be elevated only in CSF. This “cerebral” lactic acidosis may present more indolently. When blood lactate is elevated, the ratio of blood lactate to pyruvate can help narrow the differential diagnosis. The ratio is low to normal (10 to 20) in PDH deficiency, may be modestly elevated in PC type B deficiency (see later), but may be greatly elevated (>25) in an ETC defect. This ratio reflects the oxidation–reduction state of the mitochondria. When calculating this

CHAPTER 22  Inborn Errors of Carbohydrate, Ammonia, Amino Acid, and Organic Acid Metabolism 

it is important to ensure the units of the two compounds are the same. These conditions are not identified through NBS, and patients will present symptomatically unless there has been a prior affected family member such as an older affected sibling.

Pyruvate Dehydrogenase Complex Deficiency The PDH complex converts pyruvate, which is derived from the catabolism of glucose, to acetyl-CoA, which enters the TCA cycle at citrate synthase. Severe PDH deficiency may manifest in the neonatal period with profound lactic acidosis and a low to normal lactate-to-pyruvate ratio. Patients may have moderately elevated plasma ammonia and congenital brain anomalies including an absent or underdeveloped corpus callosum and heterotopias. They are hypotonic and may require mechanical ventilation. The prognosis is poor, even with early recognition and intervention. Importantly, the high concentration dextrose-containing IV and enteral empiric therapy that may be life-saving for a child with a possible organic aciduria or urea cycle defect exacerbates the lactic acidosis in the neonate with PDH deficiency or other mitochondrial energy metabolism disorders. This worsening may suggest a primary energy metabolism disorder in the neonate. A possible diagnosis of PDH deficiency is inferred from the patient presentation, the clinical course, and the results of routine and specialized biochemical laboratory testing. Alanine will likely be elevated on plasma amino acid analysis, and TCA cycle intermediates may be elevated in the urine organic acid analysis. There is no specific diagnostic compound that identifies this disorder. The diagnosis is made through abnormal enzyme analysis in skin fibroblasts or white blood cells and/or by DNA testing. The majority of individuals have a mutation in the PDHA1 gene, which encodes the E1-α subunit of the PDH enzyme complex. This is an X-linked dominant condition, and both males and females are affected (Patel et al., 2012). PDH is a large, multisubunit complex. It contains three enzymatic subunits and several regulatory subunits, including a phosphatase and a kinase. The first enzymatic step is a decarboxylation reaction catalyzed by a heterodimeric system consisting of the E1-α subunit and E1-β. All other subunits, including E1-β, result in autosomal recessive inheritance. Defects in all the known genes have been reported, and DNA sequencing is available, but mutations in PDHA1 account for 80% of cases of PDH deficiency. The majority of patients are indolent on clinical presentation with developmental delay and an MRI indicative of Leigh disease. This group of patients often responds well biochemically to a high-fat and low-carbohydrate, or ketogenic, diet. Fat, as acetylCoA, enters the energy pathway after the block, whereas glucose must traverse the defective PDH enzymatic reaction to provide energy. Defects of the PDH complex because of defects in the two other enzyme subunits, the activating and deactivating enzymes and a structural protein that binds one subunit (E3 binding protein), are rarer. These usually result in chronic psychomotor retardation syndrome in late infancy and childhood. Deficiency of the E3 subunit of the PDH complex has pleiotropic biochemical effects, because the subunit is a component of two other dehydrogenase complexes: the BCKAD complex and the α-ketoglutarate dehydrogenase complex of the TCA cycle. Therefore these patients have elevated BCAAs as in MSUD, which is due to BCKAD deficiency, as well as elevated TCA cycle metabolites because of α-ketoglutarate dehydrogenase complex deficiency. Most patients with E3 deficiency present after the newborn period and have

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progressive neurodegenerative disease. The key laboratory findings are the elevation of lactic acid in blood with elevated pyruvate and a low lactate-to-pyruvate ratio, elevated BCAAs on plasma amino acid analysis, and detection of α-ketoglutarate and BCAA metabolites in urine organic acid analysis. PDH phosphatase deficiency is a rare cause of CLA. Apart from E3 deficiency, defects in the PDH complex are responsive to the ketogenic diet. In addition to E3 deficiency there is another class of defects that affects PDH and other enzyme complexes, including BCKAD and α-ketoglutarate dehydrogenase complex, because of the requirement for lipoate in these and the complex synthesis of lipoate. Defects in eight genes encoding proteins required for lipoate synthesis have been reported, and these may present as CLA (Tort et al., 2016). Symptoms are variable and may be characteristic of the specific genetic defect. In an early-onset presentation, symptoms can include seizures, encephalopathy, and cardiomyopathy (Tort et al., 2016).

Pyruvate Carboxylase Deficiency PC is involved in gluconeogenesis and adds bicarbonate to pyruvate to form oxaloacetate, a compound also involved in replenishing intermediates of the TCA cycle. PC is one of the four carboxylases that are biotin-requiring enzymes. There are three main types of PC deficiency. Type A is characterized by lactic acidosis in the newborn period and delayed development, and the disease has a chronic course. The catastrophic form of the disorder is type B where the neonate is acutely ill in the first week of life, is encephalopathic, and develops severe metabolic acidosis with lactic acidosis and hyperammonemia. The mortality rate in this form of PC deficiency is high. Type C is considered intermittent and benign (Wang and De Vivo, 1993). Most patients with the type B form of PC deficiency have been of French or English background. The blood lactate-to-pyruvate ratio is normal in type A as both lactate and pyruvate are comparably elevated, while patients with type B often have an elevated lactateto-pyruvate ratio. Because oxaloacetate produces aspartate, which then combines with citrulline to create argininosuccinate through the urea cycle, PC deficiency leads to elevations of plasma citrulline and plasma ammonia. Although PC is an important enzyme in gluconeogenesis, hypoglycemia is not common. The liver may be enlarged. The prognosis is poor. Enzyme testing may be performed in white blood cells or fibroblasts. DNA mutational analysis may also be performed for diagnosis.

Electron Transport Chain Defects Oxidative phosphorylation results in the generation of ATP and is the central process performed by mitochondria. Genetic defects affecting the tightly coupled and regulated process of ATP generation may have profound effects on one or more organ systems. Derivatives of nutrients such as pyruvate and fatty acids are converted to carbon dioxide in mitochondria. The energy derived from this is harnessed by allowing the reducing equivalents (as NADH or FADH2, which are derived from such metabolism) to combine with oxygen to form water and, in the process the synthesis of ATP, is coupled to the flow of electrons down the ETC. The important components in the mitochondrial respiratory chain are complex I (NADH dehydrogenase), complex II (ETF dehydrogenase), complex III (cytochromes b, c1), and the terminal complex in this chain, complex IV (cytochrome c oxidase). In addition, there is a complex V (ATP synthetase) and an adenine

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nucleotide translocase that permit transport of adenosine diphosphate into, and ATP out of, the mitochondria. Complex II is involved primarily in fatty acid oxidation and oxidation of succinate derived from the TCA cycle, because the reducing equivalents extracted from fatty acids, glutaric acid, and succinate flow from ETF into complex II. Early understanding of the molecular mechanisms that produce ETC disturbances concerned those attributed to mutations of mitochondrial DNA (mtDNA—a small circular DNA molecule located within the mitochondria) genes, although in recent years multiple new disorders that effect the ETC caused by nuclear (chromosomal) encoded genes have been identified through DNA sequencing. mtDNA is important in production of the subunits of each respiratory chain complex as at least one subunit is encoded by the mtDNA except for complex II. CLA caused by defects in ETC components can be due to either nuclear or mtDNA encoded subunits, which is an important factor in genetic counseling of families of affected children. In addition to the structural components of a respiratory chain complex, defects in genes encoding proteins responsible for the assembly of the protein subunits into functional complexes can also cause lactic acidosis. Nuclear DNA encodes these assembly proteins, and defects in more than 1000 genes can result in ETC deficiency (Parikh et al., 2015). The relationship between phenotype and a specific mtDNA mutation is not straightforward, due, at least in part, to heteroplasmy (the proportion of mutant and nonmutant mtDNA molecules within each cell, each of which contain many mitochondria that also each contain multiple copies of mtDNA). Mitochondria and their mtDNA are inherited solely from the mother. Random segregation of mitochondria having greater or fewer mtDNA mutations as oocytes are formed leads to a “bottleneck effect” in which the fetus has a higher concentration of cells with mutant mtDNA than the mother, who may have little or no mutant mtDNA detectable in blood. Often there is a different proportion of defective mitochondria in different cells and different tissues, and, crucially, there is a tissue-specific “threshold effect”; that is, a certain proportion of mutant mtDNA molecules must be present to have clinical consequences in a given tissue (Wallace et al., 1988; Parikh et al., 2015). The disorders caused by nuclear DNA gene mutations are most often autosomal recessive, and they comprise the majority of ETC disease presenting in neonates and infants, with a minority resulting from mtDNA gene mutations with a maternal inheritance pattern. With the exception of neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP, caused by a mutation at position 8993 of the mtDNA), only a minority of diseases caused by mtDNA mutations manifest in the newborn period (Wong, 2007). Other examples of syndromes caused by mtDNA mutations are MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, mtDNA position 3243) and MERRF (myoclonic epilepsy with ragged-red fibers, position 8344) syndromes, Leber hereditary optic neuropathy (Wallace et al., 1988), and sporadic deletion– duplication syndromes such as Pearson marrow–pancreas syndrome (Di Donato, 2009). Important mitochondrial energy metabolism disorders that affect infants include CLA, the most dramatic form, with presentation often in the first few days of life during which there is marked lactic acidosis (Carrozzo et al., 2007; Gibson et al., 2008); subacute necrotizing encephalomyopathy or Leigh disease that classically presents at later than 3 months of age but can present earlier; Alpers disease presenting with seizures and liver disease; benign infantile mitochondrial myopathy, cardiomyopathy, or both; lethal infantile mitochondrial disease; lethal infantile

cardiomyopathy; and Pearson syndrome. The hallmarks of mitochondrial disease are often multisystem involvement and lactic acidosis, but involvement of only one organ system and the absence of lactic acidosis do not exclude it. Important classes of mitochondrial disorders include nuclear encoded mtDNA depletion syndromes resulting from defects in mtDNA replication component proteins or in the availability of nucleotides for DNA replication, which may include fatal hepatopathy (El-Hattab and Scaglia, 2013; Mayr et al., 2015). Another class is the defects in lipoate synthesis, including those of iron–sulfur protein synthesis (Tort et al., 2016). A potentially treatable class is that of coenzyme Q10 biosynthesis diagnosed by DNA testing of nuclear genes or by coenzyme Q10 levels in muscle. This includes a severe infantile multisystem disease, and it is important to identify these defects as they are one of the few classes of mitochondrial disorders in which administration of coenzyme Q10 may be effective (Quinzii and Hirano, 2011). The diagnostic tools include measurement of plasma lactate and pyruvate and analysis of urine organic and plasma amino acids. CSF lactate may be measured by lumbar puncture and by magnetic resonance spectroscopy during MRI. The current availability of mtDNA sequencing panels and whole exome sequencing with full sequencing of the mitochondrial genome has decreased the use of muscle biopsy. However, histologic analysis of muscle tissue by light and electron microscopy and mitochondrial respiratory chain complex assay on either fresh (preferred, but infrequently available) or flash-frozen tissue may be of aid in diagnosis. In many cases however, DNA sequencing has replaced muscle biopsy as a first-line test for suspected mitochondrial disease (Parikh et al., 2015). In fatal cases, rapid (metabolic) autopsy and proper preservation of tissue specimens are essential if functional assays are to be performed. DNA testing can also be performed on tissues.

Benign Infantile Mitochondrial Myopathy, Cardiomyopathy, or Both Benign infantile mitochondrial myopathy is associated with congenital hypotonia and weakness at birth, feeding difficulties, respiratory difficulties, and lactic acidosis. In this poorly understood disorder, only skeletal muscle appears to be affected, and histochemical analyses show a cytochrome c oxidase deficiency that returns to normal levels after 1 to 3 years of age. A nuclear DNA mutation in a gene-encoding fetal isoform of an ETC polypeptide specific for muscle oxidative phosphorylation was hypothesized to be the cause of this. A developmental switch from the defective fetal gene to the adult form may be responsible for the gradual improvement. It was thought to be the only example of a developmental defect in oxidative phosphorylation that is probably nuclear encoded and in which the treatment is supportive during the early newborn period to prevent death from respiratory disease. A study suggested the etiology may be due to a maternally inherited homoplasmic m.14674T>C or T>G mitochondrial tRNAGlu mutation or may be due to mutations in the nuclear gene TMRU (Horvath et al., 2009; Uusimaa et al., 2011). The form also associated with cardiomyopathy may be a variant of the benign isolated myopathy and involves striated muscle in both skeletal and cardiac muscle. It manifests in the newborn period with lactic acidosis and a cardiomyopathy that improves during the first year of life. The exact gene defect is unknown. More attention must be paid to these two disease entities because with early optimal medical care affected infants may have an excellent prognosis.

CHAPTER 22  Inborn Errors of Carbohydrate, Ammonia, Amino Acid, and Organic Acid Metabolism 

Lethal Infantile Mitochondrial Disease Infants with lethal infantile mitochondrial disease are severely ill in the first few days or weeks of life or in the extended newborn period. They exhibit hypotonia, muscle weakness, failure to thrive, and severe lactic acidosis. Death often occurs by 6 months of age and almost always is associated with overwhelming lactic acidosis. Skeletal muscle shows lipid and glycogen accumulation and abnormally shaped mitochondria on electron microscopic examination. Hepatic dysfunction may be a prominent finding in these patients. Generalized proximal renal tubular dysfunction may occur, leading to renal Fanconi syndrome. The ETC defects reported in these patients include defects in complexes I, III, and IV. Genes responsible for combined ETC defects continue to be identified (Mayr et al., 2015).

Leigh Disease: Subacute Necrotizing Encephalomyelopathy

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1993). Skeletal muscle shows abnormal mitochondrial morphology and deficiencies of respiratory chain complexes III and IV. The TAZ gene encodes tafazzin, a cardiolipin acyltransferase, which leads to disruption of the inner mitochondrial membrane and disruption of ETC function. The accumulation of NADH and FADH2 inhibit the TCA cycle, driving lactic acidosis, the development of muscle weakness, and cardiomyopathy. Urine organic acid analysis will show an increased urinary excretion of 3-methylglutaconic acid. Barth syndrome is also known as 3-methylglutaconic aciduria type II but is genetically distinct from primary 3-methylglutaconic aciduria type I, caused by mutations in AUH involved in leucine metabolism, and other forms of 3-methylglutaconic aciduria (Gaspard and McMaster, 2015). Patients must be supported from birth to early infancy as acute neonatal presentations may have lactic acidosis, hypoglycemia, hyperammonemia, and liver dysfunction. Fetal loss and stillbirth have also been reported. Treatment includes standard support for heart failure and neutropenia as well as nutrition support and physical therapy (Ferreira et al., 1993).

Leigh disease is a progressive neurodegenerative disorder with severe hypotonia, seizures, extrapyramidal movement disorder, optic atrophy, and defects in automatic ventilation or respiratory control (Baertling et al., 2014). Generally, disease onset is outside of the neonatal period, but symptoms may be evident in the first months of life. There are more than 70 genetic defects known to be associated with Leigh disease (Gerards et al., 2016). These include defects in the PDH complex, ETC structural proteins, assembly factors of individual ETC complexes, coenzyme Q10 biosynthesis, biotinidase, and others. MRI characteristically shows bilateral symmetrical T2-weighted hyperintense lesions in the basal ganglia. One disorder with features of Leigh disease is biotin–thiamine-responsive basal ganglia disease caused by SLC19A3 deficiency, and empiric biotin and thiamine should be trialed (Baertling et al., 2014). Clinical findings in infants with Leigh disease include optic atrophy, ophthalmoplegia, nystagmus, respiratory abnormalities, ataxia, hypotonia, spasticity, seizures, developmental delay, psychomotor retardation, myopathy, and renal tubular dysfunction. Some patients may manifest hypertrophic cardiomyopathy, liver dysfunction, and microcephaly. The neuropathologic lesions include demyelination, gliosis, necrosis, relative neuronal sparing, and capillary proliferation in specific brain lesions.

Early Lethal Lactic Acidosis

Pearson Syndrome

Baumgartner MR, Horster F, Dionisi-Vici C, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014;9:130. Chien YH, Lee NC, Chen CA, et al. Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. J Pediatr. 2015;166(4):985-991.e981-982. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. Kishnani PS, Austin SL, Abdenur JE, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014;16(11):e1. Mayorandan S, Meyer U, Gokcay G, et al. Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Orphanet J Rare Dis. 2014;9:107. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17(9):689-701. Patel KP, O’Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012;106(3):385-394.

One class of mitochondrial disorders that is genetic but not familial is caused by spontaneous mtDNA deletions or duplications. These include Kearns–Sayre syndrome and chronic progressive external ophthalmoplegia, which manifest in older individuals. The manifestation in early infancy is Pearson syndrome. This disorder manifests with anemia, ringed sideroblasts, and exocrine pancreatic dysfunction. This disease of the bone marrow can lead to death in infancy. However, patients able to recover or who benefit from aggressive therapy may demonstrate other signs of this systemic disorder in late infancy or childhood, such as poor growth, pancreas dysfunction, mitochondrial myopathy, lactic acidosis, and progressive neurologic damage, and develop Kearns–Sayre syndrome (DiMauro and Hirano, 1993).

Barth Syndrome Barth syndrome is an X-linked disorder associated with cardiomyopathy, skeletal muscle disease, and neutropenia (Ferreira et al.,

In some patients with primary disturbances of mitochondrial ETC, massive lactic acidosis develops within 24 to 72 hours of birth. Commonly the condition is untreatable, because it is relentless and unresponsive to buffer therapy (Danhauser et al., 2015). Dialysis may be helpful but is not a cure and is not feasible in all patients. Often, affected infants have no obvious organ damage early in the course or evidence of malformations. In addition, acidemia per se can easily cause the coma or impaired cardiac contractility that may be encountered. Some infants have survived with aggressive therapy, and specific treatments can include thiamine, biotin, riboflavin, coenzyme Q10, or carnitine (Danhauser et al., 2015). Overall prognosis is likely poor, and the care of neonates with severe lactic acidosis is difficult as the prognosis is unclear. Decisions regarding management must be individualized, because the mitochondrial dysfunction and resultant pathophysiology can vary among infants, and expedited nuclear and mitochondrial DNA testing, to facilitate diagnosis and therefore guide prognosis, should be considered.

Suggested Readings

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Spiekerkoetter U. Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening. J Inherit Metab Dis. 2010;33(5):527-532. Strauss KA, Puffenberger EG, Morton DH. Pagon RA, Adam MP, Ardinger HH, et al., eds. Maple Syrup Urine Disease. GeneReviews(R). Seattle (WA): University of Washington, Seattle; 1993. Van Calcar SC, Bernstein LE, Rohr FJ, Scaman CH, Yannicelli S, Berry GT. A re-evaluation of lifelong severe galactose restriction for the

nutrition management of classic galactosemia. Mol Genet Metab. 2014;112(3):191-197. Vockley J, Andersson HC, Antshel KM, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16(2):188-200. Complete references used in this text can be found online at www .expertconsult.com

CHAPTER 22  Inborn Errors of Carbohydrate, Ammonia, Amino Acid, and Organic Acid Metabolism 

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PART V I  Metabolic Disorders of the Newborn

Vockley J, Ensenauer R. Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity. Am J Med Genet C Semin Med Genet. 2006; 142c:95-103. Waisbren SE, Potter NL, Gordon CM, et al. The adult galactosemic phenotype. J Inherit Metab Dis. 2012;35:279-286. Wallace DC, Zheng XX, Lott MT, et al. Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell. 1988;55:601-610. Wang D, De Vivo D. 1993. Pyruvate carboxylase deficiency. GeneReviews. (Internet). https://www.ncbi.nlm.nih.gov/books/NBK6852/. Posted June 2, 2009. Updated July 30, 2015. Welling L, Bernstein LE, Berry GT, et al. International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up. J Inherit Metab Dis. 2017;40(2):171-176. Wieser T, Deschauer M, Olek K, Hermann T, Zierz S. Carnitine palmitoyltransferase II deficiency: molecular and biochemical analysis of 32 patients. Neurology. 2003;60:1351-1353. Wilcken B. Fatty acid oxidation disorders: outcome and long-term prognosis. J Inherit Metab Dis. 2010;33:501-506. Wilcken B, Haas M, Joy P, et al. Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study. Lancet. 2007;369:37-42. Wilcken B, Wiley V, Hammond J, Carpenter K. Screening newborns for inborn errors of metabolism by tandem mass spectrometry. N Engl J Med. 2003;348:2304-2312. Wilson GN, De Chadarevian JP, Kaplan P, Loehr JP, Frerman FE, Goodman SI. Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy. Am J Med Genet. 1989;32:395-401. Winchester B, Bali D, Bodamer OA, et al. Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting. Mol Genet Metab. 2008;93:275-281.

Wolf B. 1993. Biotinidase deficiency. GeneReviews. (Internet). https://www .ncbi.nlm.nih.gov/books/NBK1322/. Posted March 24, 2000. Updated June 9, 2016. Wolf B. Clinical issues and frequent questions about biotinidase deficiency. Mol Genet Metab. 2010;100:6-13. Wolfe L, Jethva R, Oglesbee D, Vockley J. 1993. Short-chain acyl-coA dehydrogenase deficiency. GeneReviews. (Internet). https://www.ncbi.nlm .nih.gov/books/NBK63582/. Posted September 22, 2011. Updated August 7, 2014. Wong LJ. Pathogenic mitochondrial DNA mutations in protein-coding genes. Muscle Nerve. 2007;36:279-293. Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M. Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Hum Mutat. 2006;27:626-632. Yang BZ, Mallory JM, Roe DS, et al. Carnitine/acylcarnitine translocase deficiency (neonatal phenotype): successful prenatal and postmortem diagnosis associated with a novel mutation in a single family. Mol Genet Metab. 2001;73:64-70. Yu HC, Sloan JL, Scharer G, et al. An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1. Am J Hum Genet. 2013;93:506-514. Zhang H, Kallwass H, Young SP, et al. Comparison of maltose and acarbose as inhibitors of maltase-glucoamylase activity in assaying acid alpha-glucosidase activity in dried blood spots for the diagnosis of infantile Pompe disease. Genet Med. 2006;8:302-306. Zytkovicz TH, Fitzgerald EF, Marsden D, et al. Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program. Clin Chem. 2001;47:1945-1955.

23 

Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and Smith–Lemli–Opitz Syndrome Presenting in the Neonate JANET A. THOMAS, CHRISTINA LAM, AND GERARD T. BERRY

KEY POINTS

CONTROVERSY BOX

• Lysosomal storage diseases (LSDs) may present in the extended neonatal period. Findings may include nonimmune hydrops fetalis, brain disease and seizures, cherry-red spot, dysmorphic facial features, dysostosis multiplex, and/or hepatomegaly. An LSD may be diagnosed via an enzyme assay and/or DNA sequencing; newborn screening (NBS) for LSDs has generated ethical and moral concerns, as well as controversy. • Many of the LSDs may be treated with enzyme replacement therapy (ERT). • The phenotypic spectrum of glycosylation disorders is broad and ranges from mild to severe and from single organ system to multisystem disease; glycosylation defects should be considered in any unexplained clinical condition but especially in multiorgan disease with neurologic involvement. • Most glycosylation disorders have been diagnosed molecularly since the advent of clinical next-generation sequencing testing. • Treatment of glycosylation defects is mainly supportive, with the exceptions of more targeted therapies being available for MPI-CDG, SLC35C1-CDG, PIGM-CDG, and PGM1-CDG. • Peroxisomal disorders are a broad and heterogeneous group of inherited diseases that result from the absence or dysfunction of one or more peroxisomal enzymes. • Features are typically evident in the newborn and are most often multisystem features, including craniofacial dysmorphism, neurologic dysfunction, including hearing and vision dysfunction, hepatodigestive dysfunction, renal cysts, and skeletal abnormalities. • Diagnosis of peroxisomal disorders is best made by next-generation sequencing techniques following abnormal biochemical screening test findings. • Treatment of individuals with peroxisomal disorders is largely symptomatic and supportive. • Smith–Lemli–Opitz syndrome (SLOS) is a multisystemic, developmental, and dysmorphic disorder with a wide clinical spectrum caused by a defect in cholesterol biosynthesis. • Diagnosis of SLOS is based on elevated 7-dehydrocholesterol and 8-dehydrocholesterol levels in the blood. • Treatment of SLOS mainly involves supportive management and exogenous cholesterol supplementation.

Newborn Screening for Lysosomal Storage Diseases Certain physicians and ethicists consider it premature to mandate state newborn screening for lysosomal storage diseases such as Krabbe disease, as the natural history of each disease with its different genotypes and phenotypes is not known and improvement in outcome with early intervention is not proven. In other disorders the presentation is later in life and not in the newborn period (e.g., Fabry disease) and thus is not consistent with the original paradigm of newborn screening. In addition, many states do not have the human resources or financial resources to ensure an accurate diagnosis and proper long-term medical care. An opposing view is that it is our moral duty to treat these patients and alleviate suffering as soon and as best as possible and to reduce or eliminate the diagnostic odyssey that many individuals suffer before diagnosis.

Suggested Readings Matern D, Gavrilov D, Oglesbee D, et al. Newborn screening for lysosomal storage disorders. Semin Perinatol. 2015;39:206-216. Ross LF. Newborn screening for lysosomal diseases: an ethical and policy analysis. J Inherit Metab Dis. 2012;35:627-634. Salveson R. Expansion of the New York State newborn screening panel and Krabbe disease: a systematic program evaluation. Columbia University Academic Commons. 2011. https://doi.org/10.7916/D8J96D9C. Wasserstein MP, Andriola M, Arnold G, et al. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet Med. 2016;18(12):1235-1423.

L

ysosomal storage disorders (LSDs), peroxisomal disorders, congenital disorders of glycosylation (CDGs), and Smith– Lemli–Opitz syndrome (SLOS) are single-gene disorders, most of which demonstrate autosomal recessive inheritance. The combined incidence of LSDs has been reported to be 1 in 1500 to 1 in 8000 live births in the United States, Europe, and Australia (Stone and Sidransky, 1999; Winchester et al., 2000; Wenger et al., 2003; Fletcher, 2006; Meikle et al., 2006; Staretz-Chacham et al., 2009). The incidence of peroxisomal disorders is estimated to be more than 1 in 20,000. The most current estimate for SLOS 253

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PART V I  Metabolic Disorders of the Newborn

Case Study 1

Case Study 2

C.J. was a 2200 g girl born to a 24-year-old mother (third pregnancy, second viable child) after a 32-week gestation by cesarean delivery performed for fetal distress. The pregnancy was complicated by the finding on ultrasonography of fetal hydrops and ascites and possible hepatosplenomegaly at 24 weeks’ gestation. Fetal blood sampling showed a hematocrit of 31% and elevations of γ-glutamyltransferase and aspartate transaminase values. The results of viral studies were negative and chromosomes were normal. At delivery, the newborn was limp and blue, with a heart rate of 60 beats per minute. Physical examination and chest radiograph showed marked abdominal distention, hepatosplenomegaly, multiple petechiae and bruises, a bell-shaped thorax, generalized hypotonia, talipes equinovarus, contractures at the knees, a large heart, and hazy lung fields with low volumes. Disseminated intravascular coagulopathy and evidence of liver disease developed rapidly, with elevated aspartate transaminase and γ-glutamyltransferase levels and increasing hyperbilirubinemia. The patient received mechanical ventilatory support and antibiotics for possible sepsis. The results of evaluations for bacterial and viral agents were negative. Metabolic studies, including studies of ammonia, lactate, very long chain fatty acids, and urine amino and organic acids, yielded unremarkable measurements. The white blood cells were noted to have marked toxic granularity consistent with overwhelming bacterial sepsis or metabolic storage disease. The patient experienced continued cardiorespiratory deterioration, had bilateral pneumothoraces and pneumopericardium, and died on the third day of life. Consent for autopsy was obtained from the family. A standard autopsy was performed and showed the presence of large, membranebound vacuoles within hepatocytes, endothelial cells, pericytes, and bone marrow stromal cells, which are typical of a metabolic storage disorder. Similar cells were also found within the placenta. There was no evidence of an infectious cause. Unfortunately, because a lysosomal storage disorder was not considered as a possible cause at the time of death, no frozen tissue or cultured fibroblasts were available to pursue the diagnosis. As a result of efforts by a research laboratory and the recurrence of disease in the couple’s subsequent pregnancy, a diagnosis of β-glucuronidase deficiency, or mucopolysaccharidosis type VII, was confirmed.

M.E. was born by normal spontaneous vaginal delivery, at term according to dates based on early ultrasonography, with a weight of 2200 g, a length of 45 cm, and a head circumference of 31.5 cm. On the basis of physical examination, the gestational age was assessed as 36 weeks. A heart murmur was noted, and investigation showed the presence of a small ventricular septal defect with no hemodynamic significance. Submucous cleft palate was noted. Examination for dysmorphic features showed simple, posteriorly rotated ears, mild epicanthic folds, micrognathia, and unilateral simian crease. Tone was moderately decreased. Irritability and severe feeding problems were noted, and gavage feeding was required; growth was poor despite adequate intake of calories. The results of a karyotype analysis were normal, and the results of studies for velocardiofacial syndrome were negative. Vomiting developed, and further evaluation showed no acidosis, hypoglycemia, or hyperammonemia. Liver-associated values and cholesterol level were normal, as were results of studies of amino acids, organic acids, and acylcarnitine profile. Vomiting became severer and did not respond to elemental formula, and pyloric stenosis was detected. Feeding problems persisted after successful surgical correction. Delivery of more than 140 kcal/kg by gavage was poorly tolerated but resulted in weight gain; however, length and head growth remained poor. Smith–Lemli–Opitz syndrome was suggested despite the normal cholesterol value obtained on analysis in the hospital laboratory. Studies performed in a specialized laboratory showed the 7-dehydrocholesterol and 8-dehydrocholesterol values to be elevated and the cholesterol value to be decreased. Cholesterol supplementation led to some improvement in behavior and feeding. A decrease to 110 kcal/kg per day was tolerated without worsening of growth, and weight for height gradually returned to normal. A review of records confirmed that the pregnancy had been accurately dated by ultrasonography at 10 weeks’ gestation, confirming that M.E. was small for gestational age and microcephalic at birth, with subsequent growth typical of Smith–Lemli–Opitz syndrome. The incorrect assessment of gestational age as 36 weeks on examination was found to result from a failure to appreciate the effect of hypotonia on the findings for gestational age. The family was counseled about autosomal recessive inheritance, including the availability of prenatal diagnosis.

is 1 in 20,000, and a similar frequency of 1 in 20,000 is estimated for the CDGs. These four categories of metabolic diseases involve molecules important in cell membranes and share overlapping clinical presentations. The clinical presentations are heterogeneous, with a broad range of age at presentation and severity of symptoms. All are chronic and progressive. The age of onset ranges from prenatal to adulthood, and severity can range from severe disability and early death to nearly normal lifestyle and life span. For each condition, interfamilial variability is greater than intrafamilial variability. The genetic and clinical characteristics of conditions in these categories that can manifest themselves in the neonatal period (except Pompe disease, which is addressed in Chapter 22) are summarized in Tables 23.1–23.2. Important presentations that should lead the neonatologist to consider these disorders in the differential diagnosis are as follows: 1. In utero infection—hepatosplenomegaly and hepatopathy, possibly with extramedullary hematopoiesis 2. Nonimmune hydrops fetalis, ichthyotic or collodion skin, or both 3. Neurologic only—early and often difficult to control seizures, hypertonia, or hypotonia, with or without altered head size and with or without eye findings

Case Study 3 H.K. was born at term to healthy parents by cesarean delivery performed for breech presentation after an otherwise uncomplicated pregnancy. Hypotonia and dysmorphic features were noted in the delivery room, including inner epicanthic folds, flat occiput, large fontanels, shallow orbital ridges, low nasal bridge, micrognathia, redundant skin folds at the neck, and unilateral simian crease. Brushfield spots were present. Investigation of a heart murmur revealed patent ductus arteriosus and a small atrial septal defect. There was mild hepatomegaly but normal liver function, no acidosis, and no hypoglycemia. Suck was poor, and gavage feeding was required. The results of a karyotype analysis were normal, and there was no evidence of trisomy 21 in blood in 50 interphase cells examined. The option of skin biopsy to search further for evidence of mosaicism for trisomy 21 was considered. Thyroid function values were normal. Urine amino and organic acid values were normal, as was the acylcarnitine profile. Plasma very long chain fatty acid analysis showed elevation consistent with a diagnosis of Zellweger syndrome, along with a typical increase in pipecolic acid value and impaired capacity for fibroblast synthesis of plasmalogens. The baby died at 3 months of age, and autopsy showed polymicrogyria and small hepatic and renal cysts. The family was counseled about autosomal recessive inheritance, including the availability of prenatal diagnosis.

CHAPTER 23  Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and SLOS Presenting in the Neonate

Case Study 4 M.J. had hypotonia at birth after an uncomplicated pregnancy. Minor dysmorphic features were noted, including high nasal bridge, large ears, and inverted nipples. Feeding difficulties were significant, and growth was poor. The findings on head ultrasonography were unremarkable, as were those of head magnetic resonance imaging, although the radiologist questioned whether the cerebellum might be slightly small. The results of a karyotype analysis were normal. There was no acidosis or hypoglycemia, and liver enzyme values were normal; the results of amino and organic acid analyses and the acylcarnitine profile were normal. The baby was discharged on a diet providing 130 kcal/kg per day. On follow-up, growth remained poor, and development was severely delayed. At 6 months of age, she was admitted to the hospital for an episode of dehydration and irritability after gastroenteritis. Mild acidosis, borderline elevations of lactate and ammonia levels, and significant elevation of liver enzyme levels were noted over the course of the hospital stay. The liver enzyme levels remained elevated after discharge. Cardiac ultrasonography showed a small pericardial effusion, which resolved. Amino and organic acid values were normal, as was the acylcarnitine profile. Urine oligosaccharide levels showed an unusual pattern, and urine mucopolysaccharide values were normal. At 2 years of age, developmental delay remained marked, and hypotonia persisted with reflexes absent. The creatinine phosphokinase level was normal, but liver function values remained abnormal. Because mitochondrial disease was suspected, the patient was scheduled for liver biopsy, but clotting values were abnormal. A congenital disorder of glycosylation was suspected, and a transferrin assay confirmed the diagnosis. A review of neonatal records revealed a comment from a neurology consultant about the unusual distribution of fat on the buttocks and thighs of M.J. as a neonate. The family was counseled about autosomal recessive inheritance, including availability of prenatal diagnosis.

4. Coarse facial features with bone changes, dysostosis multiplex, or osteoporosis 5. Dysmorphic facial features with or without major malformations 6. Rarely, known family history or positive prenatal diagnosis Only for the last three presentations are these conditions likely to be considered early in the differential diagnosis. Most babies with these conditions are born to healthy, nonconsanguineous couples with normal family histories, and these disorders are usually considered late, if at all, as in Case Study 1.

Lysosomal Storage Disorders Lysosomes are single membrane–bound intracellular organelles that contain enzymes called hydrolases. These lysosomal enzymes are responsible for splitting large molecules into simple, lowmolecular-weight compounds, which can be recycled. The materials digested by lysosomes and derived from endocytosis and phagocytosis are separated from other intracellular materials by the process of autophagy, which is the main mechanism whereby endogenous molecules are delivered to lysosomes. The common element of all compounds digested by lysosomal enzymes is that they contain a carbohydrate portion attached to a protein or lipid. These glycoconjugates include glycoproteins, glycosaminoglycans (GAGs), and glycolipids. Glycolipids are large molecules with carbohydrates attached to a lipid moiety. Sphingolipids, globosides, gangliosides, cerebrosides, and lipid sulfates all are glycolipids. The different classes of glycolipids are distinguished from one another primarily by different polar groups at C-1. Sphingolipids are complex membrane lipids

255

composed of one molecule of each of the amino alcohol sphingosine, a long-chain fatty acid, and various polar head groups attached by a β-glycosidic linkage. Sphingolipids occur in the blood and nearly all tissues of the body, the highest concentration being found in white matter of the central nervous system (CNS). In addition, various sphingolipids are components of the plasma membrane of practically all cells. The core structure of natural sphingolipids is ceramide, a long-chain fatty acid amide derivative of sphingosine. Free ceramide, an intermediate in the biosynthesis and catabolism of glycosphingolipids and sphingomyelin, composes 16%–20% of normal lipid content of stratum corneum of the skin. Sphingomyelin, a ceramide phosphocholine, is one of the principal structural lipids of membranes of nervous tissue. Cerebrosides are a group of ceramide monohexosides with a single sugar, either glucose or galactose, and an additional sulfate group on galactose. The two most common cerebrosides are galactocerebroside and glucocerebroside. The largest concentration of galactocerebroside is found in the brain. Glucocerebroside is an intermediate in the synthesis and degradation of more complex glycosphingolipids. Gangliosides, the most complex class of glycolipids, contain several sugar units and one or more sialic acid residues. Gangliosides are normal components of cell membranes and are found in high concentrations in ganglion cells of the CNS, particularly in nerve endings and dendrites. GM1 is the major ganglioside in the brain of vertebrates. Gangliosides function as receptors for toxic agents, hormones, and certain viruses, are involved in cell differentiation, and can also have a role in cell–cell interaction by providing specific recognition determinants on the surface of cells. Ceramide oligosaccharides (i.e., globosides) are a family of cerebrosides that contain two or more sugar residues, usually galactose, glucose, or N-acetylgalactosamine. GAGs and oligosaccharides are essential constituents of connective tissue, parenchymal organs, cartilage, and the nervous system. GAGs, also called mucopolysaccharides, are complex heterosaccharides consisting of long sugar chains rich in sulfate groups. The polymeric chains are bound to specific proteins (core proteins). Glycoproteins contain oligosaccharide chains (long sugar molecules) attached covalently to a peptide core. Glycosylation occurs in the endoplasmic reticulum and Golgi apparatus. Most glycoproteins are secreted from cells and include transport proteins, glycoprotein hormones, complement factors, enzymes, and enzyme inhibitors. There is extensive diversity in the composition and structure of oligosaccharides. The degradation of glycolipids, GAGs, and glycoproteins occurs especially within lysosomes of phagocytic cells, related to histiocytes and macrophages, in any tissue or organ. A series of hydrolytic enzymes cleaves specific bonds, resulting in sequential, stepwise removal of constituents such as sugars and sulfate and degrading complex glycoconjugates to the level of their basic building blocks. LSDs most commonly result when an inherited defect causes significantly decreased activity in one of these hydrolases. Other causes are failure of transport of an enzyme, substrate, or product. Whatever the specific cause, incompletely metabolized molecules accumulate, especially within the tissue responsible for catabolism of the glycoconjugate. Additional excess storage material may be excreted in urine. The mechanisms of cellular dysfunction and damage in most LSDs remain unknown. Various hypotheses have been offered, such as a pivotal disturbance in the normal process of autophagy (Kiselyov et al., 2007; Ballabio and Gieselmann, 2009). In this pathophysiologic construct, endoplasmic reticulum membrane engulfment of cellular components, such as mitochondrial derivatives targeted for destruction, is perturbed. As a consequence,

TABLE 23.1 

Lysosomal Storage Disorders in the Newborn Period: Genetic and Clinical Characteristics of Neonatal Presentation

Disorder

Onset

Facies

Neurologic Findings

Distinctive Features

Eye Findings

Niemann–Pick A disease

Early infancy

Frontal bossing

Difficulty feeding, apathy, deafness, blindness, hypotonia

Brownish-yellow skin, xanthomas

Cherry-red spot (50%)

Niemann–Pick C disease

Birth–3 months

Normal

Developmental delay, vertical gaze paralysis, hypotonia, later spasticity

–

–

Gaucher disease type 2

In utero–6 months

Normal

Poor suck and swallow, weak cry, squint, trismus, strabismus, opsoclonus, hypertonic, later flaccidity

Congenital ichthyosis, collodion skin

–

Krabbe disease

3–6 months

Normal

Irritability, tonic spasms with light or noise stimulation, seizures, hypertonia, later flaccidity

Increased CSF protein level

Optic atrophy

GM1 gangliosidosis

Birth

Coarse

Poor suck, weak cry, lethargy, exaggerated startle, blindness, hypotonia, later spasticity

Gingival hypertrophy, edema, rashes

Cherry-red spot (50%)

Farber disease type I

2 weeks–4 months

Normal

Progressive psychomotor impairment, seizures, decreased reflexes, hypotonia

Joint swelling with nodules, hoarseness, lung disease, contractures, fever, granulomas, dysphagia, vomiting, increased CSF protein level

Grayish opacification surrounding retina in some patients, subtle cherry-red spot

Farber disease types II and III

Birth–9 months (≤20 months)

Normal

Joint swelling with nodules, hoarseness

Normal macula, corneal opacities

Farber disease type IV (neonatal)

Birth

Normal

Nodules not consistent findings

Corneal opacities (1/3)

–

Congenital sialidosis

In utero–birth

Coarse, edema

Mental retardation, hypotonia

Neonatal ascites, inguinal hernias, renal disease

Corneal clouding

Galactosialidosis

In utero–birth

Coarse

Mental retardation, occasional deafness, hypotonia

Ascites, edema, inguinal hernias, renal disease, telangiectasias

Cherry-red spot, corneal clouding

Wolman disease

First weeks of life

Normal

Mental deterioration

Vomiting, diarrhea, steatorrhea, abdominal distention, failure to thrive, anemia, adrenal calcifications

–

Infantile sialic acid storage disease

In utero–birth

Coarse, dysmorphic

Mental retardation, hypotonia

Ascites, anemia, diarrhea, failure to thrive

–

I-cell disease

In utero–birth

Coarse

Mental retardation, deafness

Gingival hyperplasia, restricted joint mobility, hernias

Corneal clouding

Mucolipidosis type IV

Birth–3 months

Normal

Mental retardation, hypotonia

–

Severe corneal clouding, retinal degeneration, blindness

Mucopolysaccharidosis type VII

In utero– childhood

Variable coarseness

Mild to severe mental retardation

Hernias

Variable corneal clouding

–, Not seen; +, typically present, usually not severe; ++, usually present and moderately severe; +++, always present, usually severe; CSF, cerebrospinal fluid, HSM, hepatosplenomegaly.

Cardiovascular Findings

Dysostosis Multiplex

Hepatomegaly/ Splenomegaly

Defect

Gene Location/Molecular Findings

Ethnic Predilection

–

–

++/+

Sphingomyelinase deficiency

SMPD1 gene at 11p15.4; three of 18 mutations account for approximately 92% of mutant alleles in the Ashkenazi population

1 : 40,000 in Ashkenazi Jews with carrier frequency of 1 : 60

–

–

+/++

Abnormal cholesterol esterification

NPC1 gene at 18q11 accounts for >95% of cases; HE1 gene mutations may account for remaining cases

Increased in French Canadians of Nova Scotia and Spanish Americans in the southwest United States

–

–

+/++

Glucocerebrosidase deficiency

1q21; large number of mutations known; five mutations account for approximately 97% of mutant alleles in the Ashkenazi population but approximately 75% in the non-Jewish population

Panethnic

–

–

–/–

Galactocerebrosidase deficiency

14q 24.3-q32.1; >60 mutations with some common mutations in specific populations

Increased in Scandinavian countries and in a large Druze kindred in Israel

–

+

+/+

β-Galactosidase deficiency

3pter-3p21; heterogeneous mutations; common mutations in specific populations

Panethnic

Occasional

–

Hepatomegaly in 50%, splenomegaly less common

Lysosomal acid ceramidase

8p21.3-22; nine disease-causing mutations identified

Panethnic

–

–

HSM less common than in type I

8p21.3-p22

Panethnic

++/++

Unknown

Panethnic

– –

+

+/+

Neuraminidase deficiency

NEU 1 gene (sialidase) at 6p21

Panethnic

Cardiomegaly progressing to failure

+

+/+

Absence of a protective protein that safeguards neuraminidase and β-galactosidase from premature degradation

20q13.1

Panethnic

–

–

+/+

Lysosomal acid lipase deficiency

10q23.2-q23.3; variety of mutations identified

Increased in Iranian Jews and in non-Jewish and Arab populations of Galilee

Congestive heart failure

+

+/+

Defective transport of sialic acid out of the lysosome

SLC17A5 gene at 6q

Panethnic

Valvular disease, congestive heart failure, cor pulmonale

++

+++/+++

Lysosomal enzymes lack mannose 6-phosphate recognition marker and fail to enter the lysosome (phosphotransferase deficiency, 3-subunit complex [α2 β2 γ2])

Enzyme encoded by two genes; α and β subunits encoded by gene at 12p; γ subunit encoded by gene at 16p

Panethnic

–

–

–/–

Unknown; some patients with partial deficiency of ganglioside sialidase

MCOLN1 gene at 19p13.2-13.3 encoding mucolipin 1; two founder mutations accounting for 95% of mutant alleles in the Ashkenazi population

Increased in Ashkenazi Jews

Variable

++

Variable

β-Glucuronidase deficiency

GUSB gene at 7q21.2-q22; heterogeneous mutations

Panethnic

258

PART V I  Metabolic Disorders of the Newborn

TABLE 23.2 

Common Clinical Features of Congenital Disorders of Glycosylation by Pathway

Pathway

Example Disorders

Neurologic

Ophthalmologic

Cardiologic

Gastroenterologic

N-linked glycosylation

PMM2-CDG, MPI-CDG, ALGx-CDG, MOGS-CDG

ID (except MPI), DD, seizures (50%), hypotonia, ataxia, dysmetria, dysarthria, peripheral neuropathy, cerebral and cerebellar atrophy, myasthenic syndrome

Strabismus, nystagmus, optic hypoplasia, retinal pigmentary changes, alacrima

Pericardial effusion, cardiomyopathy, fetal hydrops

Protein-losing enteropathy, diarrhea, failure to thrive, gastroesophageal reflux, hepatopathy with elevated AST and ALT levels, edema and hypoalbuminemia, low cholesterol level

O-linked glycosylation

GALNT3-CDG, B3GLCT-CDG, POMK-CDG, EXT1-CDG, CHST-CDG

ID (not universal), DD, congenital and later-onset muscular dystrophy, hypotonia, polymicrogyria lissencephaly

Peters plus syndrome, other structural eye abnormalities, glaucoma, isolated macular corneal dystrophy, corneal opacity, cataracts

Mixed glycosylation

COGx-CDG, TMEMx-CDG,

Seizures, ID (not universal), DD, microcephaly, hypotonia, cortical and cerebellar atrophy

All findings seen in N-linked pathway possible

GPI anchor disorder

PIGx-CDG, PGAPx-CDG

Seizures, ID, DD, macrocephaly, hypotonia

Lipid glycosylation

ST3GAL5-CDG (Amish infantile epilepsy syndrome)

Seizures, ID, DD, hypotonia, diffuse brain atrophy, irritability, microcephaly

Failure to thrive

Cardiomyopathy, congenital structural heart defects

All findings seen in N-linked pathway possible, isolated polycystic liver disease, high cholesterol level, cholestatic liver disease, prenatal growth retardation

Congenital heart defects, cardiomyopathy

Optic atrophy, cortical visual impairment

Failure to thrive

ALT, Alanine transaminase; AST, aspartate transaminase; DD, developmental disability; GPI, glycosylphosphatidylinositol; ID, intellectual disability; IGF1, insulin-like growth factor 1.

deleterious pathways become activated, leading to unwanted ubiquitination of targeted molecules and apoptosis. LSDs are classified according to the stored compound. The clinical phenotype depends partially on the type and amount of storage substance. There are more than 50 different LSDs, and a significant fraction, approximately 20 LSDs, may have manifestations in the newborn (Staretz-Chacham et al., 2009). The disorders selected for discussion in this chapter are all known to manifest themselves in the neonatal period.

Clinical Presentations Table 23.1 summarizes the clinical characteristics of the neonatal presentations of LSDs.

Niemann–Pick A Disease (Acute, Sphingomyelinase Deficient) Etiology

Niemann–Pick A disease is caused by a deficiency of sphingomyelinase. Sphingomyelinase catalyzes the breakdown of sphingomyelin

to ceramide and phosphocholine, and its deficiency results in sphingomyelin storage within lysosomes. Cholesterol is also stored, suggesting that its metabolism is tied to that of sphingomyelin. Sphingomyelin normally composes 5%–20% of phospholipids in the liver, spleen, and brain, but in these disorders it can compose up to 70% of phospholipids. Individuals with Niemann–Pick A disease usually have enzyme activity less than 5% of normal. Clinical Features

Clinical features of this disorder may appear in utero or up to 1 year of age. Affected infants usually have massive hepatosplenomegaly (hepatomegaly greater than splenomegaly), constipation, feeding difficulties, and vomiting, with consequent failure to thrive. Patients eventually appear strikingly emaciated with a protuberant abdomen and thin extremities. Neurologic disease is evident by 6 months of age, with hypotonia, decrease or absence of deep tendon reflexes, and weakness. Loss of motor skills, spasticity, rigidity, and loss of vision and hearing occur later. Seizures are rare. A retinal cherry-red spot is present in about half of cases, and the electroretinographic findings are abnormal. Respiratory infections are

CHAPTER 23  Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and SLOS Presenting in the Neonate

259

KEY FEATURES BY SYSTEM

Hematologic

Renal

Endocrine

Dermatologic

Musculoskeletal/Other

Diagnostic Screen

Factors II, V, VII, VIII, IX, X, and XI, antithrombin III, protein C, protein S deficiency, increased bleeding tendency, thrombotic events, hypogammopathy, coagulopathy and thrombosis

Hyperechoic kidneys, microcystic changes, proteinuria

Abnormal thyroid function test findings, short stature, IGF1 deficiency, hypogonadotropic hypogonadism, hyperinsulinemic hypoglycemia

Lipodystrophy, hypohidrosis

Osteopenia, kyphoscoliosis, dysmorphic features, skeletal dysplasia

Transferrin profiling, urine oligosaccharide analysis

Tumoral calcinosis with phosphatemia

Loose skin, Dowling–Degos disease

Skeletal dysplasia, short stature, Ehlers–Danlos syndrome, hypermobility, exostoses, elevated creatine kinase, dysmorphic facies

Ichthyosis, cutis laxa, hypohidrosis

Skeletal dysplasia, dysmorphic features, elevated creatine kinase level

Transferrin profiling with apolipoprotein CIII profiling

Dysmorphic features, multiple congenital anomalies

Flow cytometry studies using cell surface markers such as FLAER and CD59 on granulocytes, lymphocytes, etc.

Isolated leukocyte adhesion deficiency, isolated congenital dyserythropoietic anemia type II, immunodeficiency

Obstructive uropathy, micropenis, hypospadias

Accelerated linear growth, advanced bone age, with or without hyperphosphatasia Dyspigmentation, “salt and pepper” pattern on skin macules

common. The skin may have an ochre or brownish-yellow color, and xanthomas have been observed. Radiographic findings consist of widening of medullary cavities, cortical thinning of long bones, and osteoporosis. In the brain and spinal cord, neuronal storage is widespread, leading to cytoplasmic swelling together with atrophy of cerebellum. Bone marrow and tissue biopsy samples may show foam cells or sea-blue histiocytes, which represent lipid-laden cells of the monocyte–macrophage system. Similarly, vacuolated lymphocytes or monocytes may be present in peripheral blood. Tissue cholesterol levels may be threefold to tenfold that of normal, and patients may have a microcytic anemia and thrombocytopenia. Death occurs by 2–3 years of age.

Niemann–Pick C Disease Etiology

Niemann–Pick C disease is caused by an error in the intracellular transport of exogenous low-density lipoprotein (LDL)-derived cholesterol, which leads to impaired esterification of cholesterol and trapping of unesterified cholesterol in lysosomes. The incidence may be higher than 1 in 150,000 births (Wraith et al., 2009).

Cell lines from patients can be divided into two complementation groups, Niemann–Pick C (NPC)1 and NPC2, corresponding to different genes (Millat et al., 2001). In each group the primary defect is abnormal cholesterol esterification, but the enzyme responsible for cholesterol esterification—acetyl coenzyme A (CoA) acetyltransferase (ACAT)—is not deficient. The storage of sphingomyelin is secondary. It has been suggested that the defect is in transport of cholesterol out of the lysosome, making cholesterol unavailable to ACAT (Natowicz et al., 1995). Sphingomyelinase activity appears normal or elevated in most tissues but is partially deficient (60%–70%) in fibroblasts from most patients with this disorder. Storage of sphingomyelin in tissues is much less than in Niemann–Pick A or Niemann–Pick B disease and is accompanied by additional storage of unesterified cholesterol, phospholipids, and glycolipids in the liver and spleen. Only glycolipids levels are increased in the brain. Clinical Features

The age of onset, clinical features, and natural history of Niemann– Pick C disease are highly variable. Onset can occur from birth to

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18 years of age. Fifty percent of children with onset in the neonatal period have conjugated hyperbilirubinemia, which usually resolves spontaneously but is followed by neurologic symptoms later in childhood. In the severe infantile form, hepatosplenomegaly is common, accompanied by hypotonia and delayed motor development. Further mental regression is usually evident by the age of 1–1.5 years, in association with behavior problems, vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, spasticity, dementia, drooling, dysphagia, and dysarthria. Seizures are rare. Foam cells and sea-blue histiocytes may be found in many tissues. Neuronal storage with cytoplasmic ballooning, inclusions, meganeurites, and axonal spheroids are also seen. Death may occur in infancy or as late as the third decade of life. Niemann–Pick C disease can also manifest itself as fatal neonatal liver disease, often misdiagnosed as fetal hepatitis. Patients with mutations in the NPC2 gene (also known as HE1) may have remarkable features consisting of pronounced pulmonary involvement leading to early death caused by respiratory failure (Millat et al., 2001).

Gaucher Disease Type 2 (Acute Neuropathic) Etiology

Three types of Gaucher disease have been defined. Type 1, the nonneuropathic form, is the most common and is distinguished from types 2 and 3 by the lack of CNS involvement. Type 1 disease most commonly manifests itself in early childhood but may do so in adulthood. Type 2 disease, the acute neuropathic form, is characterized by infantile onset of severe CNS involvement. Type 3 disease, the subacute neuropathic form, is also late in onset, with slow neurologic progression. Almost all types of Gaucher disease are caused by a deficiency of lysosomal glucocerebrosidase and result in storage of glucocerebroside in visceral organs; the brain is affected in types 2 and 3. Although there is significant variability in clinical presentation among individuals with the same mutations, there is a clear correlation between certain mutations and clinical symptoms involving the CNS (Beutler and Grabowski, 2001). Glucocerebrosidase splits glucose from cerebroside, yielding ceramide and glucose. A few patients with Gaucher disease type 2 have a deficiency of saposin C, a cohydrolase required by glucocerebrosidase. Clinical Features

Typically, the age of onset of Gaucher disease type 2 is approximately 3 months, consisting of hepatosplenomegaly (splenomegaly predominates) with subsequent neurologic deterioration. Hydrops fetalis, congenital ichthyosis, and collodion skin, however, are well-described presentations (Lipson et al., 1991; Sidransky et al., 1992; Sherer et al., 1993; Fujimoto et al., 1995; Ince et al., 1995; Liu et al., 1988). In a review of 18 cases of Gaucher disease manifesting itself in the newborn period, Sidransky et al. (1992) found that eight patients had associated dermatologic findings and six patients had hydrops. The cause of the association of such findings in Gaucher disease is unclear, although the enzyme deficiency appears to be directly responsible (Sidransky et al., 1992). Ceramides have been shown to be major components of intracellular bilayers in epidermal stratum corneum, and they have an important role in skin homeostasis (Fujimoto et al., 1995). Therefore Gaucher disease should be considered in the differential diagnosis for infants with hydrops fetalis and congenital ichthyosis. For the subset of patients in the prenatal period or at birth, death frequently occurs within hours to days or at least within 2–3 months.

Krabbe Disease (Globoid Cell Leukodystrophy) Etiology

The synonym for Krabbe disease, globoid cell leukodystrophy, is derived from the finding of large numbers of multinuclear macrophages in cerebral white matter that contain undigested galactocerebroside. Disease is caused by a deficiency of lysosomal galactocerebroside β-galactosidase, which normally degrades galactocerebroside to ceramide and galactose. Deficiency of the enzyme results in storage of galactocerebroside. Galactocerebroside is present almost exclusively in myelin sheaths. Accumulation of the toxic metabolite psychosine, also a substrate for the enzyme, has been postulated to lead to early destruction of oligodendroglia. Impaired catabolism of galactosylceramide is also important in the pathogenesis of the disease. Clinical Features

The age of onset ranges from the first weeks of life to adulthood. The typical age of onset of infantile Krabbe disease is between 3 and 6 months, but there are cases of early onset in which neurologic symptoms are evident within weeks after birth. Symptoms and signs are confined to the nervous system; no visceral involvement is present. The clinical course has been divided into three stages. In stage I, patients who appeared relatively normal after birth exhibit hyperirritability, vomiting, episodic fevers, hyperesthesia, tonic spasms with light or noise stimulation, stiffness, and seizures. Peripheral neuropathy is present, but reflexes are increased. Stage II is marked by CNS deterioration and hypertonia that progresses to hypotonia and flaccidity. Deep tendon reflexes are eventually lost. Patients with stage III disease are decerebrate, deaf, and blind with hyperpyrexia, hypersalivation, and frequent seizures. Routine laboratory findings are unremarkable except for an elevation of the level of cerebrospinal fluid protein. Cerebral atrophy and demyelination become evident in the CNS, and segmental demyelination, axonal degeneration, fibrosis, and macrophage infiltration are common in the peripheral nervous system. The segmental demyelination of peripheral nerves is demonstrated by the finding of decreased motor nerve conduction. The white matter is severely depleted of all lipids, especially glycolipids, and nerve and brain biopsies show globoid cells. Death from hyperpyrexia, respiratory complications, or aspiration occurs at a median age of 13 months.

GM1 Gangliosidosis Etiology

Infantile GM1 gangliosidosis is caused by a deficiency in lysosomal β-galactosidase. The enzyme cleaves the terminal galactose in a β linkage from oligosaccharides, keratan sulfate, and GM1 ganglioside. Deficiency of the enzyme results in storage of GM1 ganglioside and oligosaccharides. Clinical severity correlates with the extent of substrate storage and residual enzyme activity. The same enzyme is deficient in Morquio disease type B. Clinical Features

The age of onset ranges from prenatal to adult. Infantile or type 1 GM1 gangliosidosis may be evident at birth as coarse and thick skin, hirsutism on the forehead and neck, and coarse facial features consisting of a puffy face, frontal bossing, depressed nasal bridge, maxillary hyperplasia, large and low-set ears, wide upper lip, moderate macroglossia, and gingival hypertrophy. These dysmorphic features, however, are not always obvious in the neonate. A retinal cherry-red spot is seen in 50% of patients, and corneal clouding is often observed. Shortly after birth, or by 3–6 months of age,

CHAPTER 23  Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and SLOS Presenting in the Neonate

failure to thrive and hepatosplenomegaly become evident, as does neurologic involvement with poor development, hyperreflexia, hypotonia, and seizures. Cranial imaging shows diffuse atrophy of the brain, enlargement of the ventricular system, and evidence of myelin loss in white matter. The neurologic deterioration is progressive, resulting in generalized rigidity and spasticity and sensorimotor and psychointellectual dysfunction. By 6 months of age, skeletal features are present, including kyphoscoliosis and stiff joints with generalized contractures, and striking bone changes are seen—vertebral beaking in the thoracolumbar region, broadening of shafts of the long bones with distal and proximal tapering, and widening of the metacarpal shafts with proximal pinching of four lateral metacarpals. Tissue biopsy samples demonstrate neurons filled with membranous cytoplasmic bodies and various types of inclusions as well as foam cells in the bone marrow. Death generally occurs before 2 years of age. A severe neonatal-onset type of GM1 gangliosidosis with cardiomyopathy has also been described (Kohlschütter et al., 1982).

Farber Lipogranulomatosis Etiology

Farber lipogranulomatosis results from a deficiency of lysosomal acid ceramidase. Ceramidase catalyzes the degradation of ceramide to its long-chain base, sphingosine, and a fatty acid. Clinical disease is a consequence of storage of ceramide in various organs and body fluids. Clinical Features

Four types of Farber lipogranulomatosis can manifest themselves in the neonatal period. Type I, classic disease, is a unique disorder with onset from approximately 2 weeks to 4 months of age. Patients exhibit hoarseness progressing to aphonia, feeding and respiratory difficulties, poor weight gain, and intermittent fever caused by granuloma formation and swelling of the epiglottis and larynx. Palpable nodules appear over joints and pressure points, and joints become painful and swollen. Later, joint contractures and pulmonary disease appear. Liver and cardiac involvement can occur, and patients can have a subtle retinal cherry-red spot. Severe and progressive psychomotor impairment can occur, as can seizures, decreased deep tendon reflexes, hypotonia, and muscle atrophy. Affected patients die in early infancy, usually of pulmonary disease. Type 2, or intermediate, Farber lipogranulomatosis manifests itself from birth to 9 months of age as joint and laryngeal involvement and nodules. Death occurs in early childhood. Type 3 disease (mild) manifests itself slightly later, from approximately 2 months to 20 months of age, with survival into the third decade. Clinically types 2 and 3 are both dominated by subcutaneous nodules, joint deformity, and laryngeal involvement. Liver and pulmonary involvement may be absent. Two-thirds of patients have a normal intelligence quotient. Type 4, or neonatal visceral, Farber lipogranulomatosis manifests itself at birth as hepatosplenomegaly caused by massive histiocyte infiltration of the liver and spleen, with infiltration also in the lungs, thymus, and lymphocytes. Subcutaneous nodules and laryngeal involvement may be subtle. Death occurs by 6 months of age. In all types of Farber lipogranulomatosis, tissue biopsy samples show granulomatous infiltration, foam cells, and lysosomes with comma-shaped, curvilinear tubular structures called Farber bodies. Cerebrospinal fluid protein level may be elevated in patients with type 1 disease.

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Sialidosis Etiology

Sialidosis is caused by a deficiency of neuraminidase, which is responsible for the cleavage of terminal sialyl linkages of several oligosaccharides and glycopeptides. The defect results in multisystem lysosomal accumulation of sugars rich in sialic acid. Clinical Features

Type I sialidosis is characterized by retinal cherry-red spots and generalized myoclonus with onset generally in the second decade of life. Type II is distinguished from type I by the early onset of a progressive, severe phenotype with somatic features. Type II is often subdivided into juvenile, infantile, and congenital forms. Congenital sialidosis begins in utero and manifests itself at birth as coarse features, facial edema, hepatosplenomegaly, ascites, hernias, and hypotonia and occasionally frank hydrops fetalis. Radiographs demonstrate dysostosis multiplex and epiphyseal stippling. Delayed mental development is quickly apparent. The patient may have recurrent infections. Severely dilated coronary arteries, excessive retinal vascular tortuosity, and an erythematous macular rash may also be features of this disease (Buchholz et al., 2001). Most patients are stillborn or die before 1 year of age. The age of onset for the infantile form of sialidosis ranges from birth to 12 months. The clinical features include coarse facial features, organomegaly, dysostosis multiplex, retinal cherry-red spot, and mental retardation. Death occurs by the second or third decade. In both types of sialidosis, vacuolated cells can be seen in almost all tissues, and bone marrow foam cells are present.

Galactosialidosis Etiology

Galactosialidosis results from a deficiency of two lysosomal enzymes, neuraminidase and β-galactosidase. The primary defect in galactosialidosis is a defect in the protective protein cathepsin A, an intralysosomal protein that protects the two enzymes from premature proteolytic processing. The protective protein has catalytic and protective functions, and the two functions appear to be distinct. Deficiency of the enzymes results in the accumulation of sialyloligosaccharides in tissue lysosomes and in excreted body fluids. Clinical Features

Galactosialidosis has been divided into three phenotypic subtypes on the basis of age at onset and severity of clinical manifestations. Most cases occur in adolescence and adulthood, but early infantile and late infantile presentations occur. Patients develop early infantile galactosialidosis between birth and 3 months of age, with ascites, edema, coarse facial features, inguinal hernias, proteinuria, hypotonia, and telangiectasias, and, occasionally, frank hydrops fetalis. Patients subsequently demonstrate organomegaly, including cardiomegaly progressing to cardiac failure, psychomotor delay, and skeletal changes, particularly in the spine. Ocular abnormalities can occur, including corneal clouding and retinal cherry-red spots. Death occurs at an average age of 8 months, usually from cardiac and renal failure. Galactosialidosis can be a cause of recurrent fetal loss or recurrent hydrops fetalis. Late infantile galactosialidosis manifests itself in the first months of life as coarse facial features, hepatosplenomegaly, and skeletal changes consistent with dysostosis multiplex. Cherry-red spots and corneal clouding may also be present. Neurologic involvement may be absent or mild. Valvular heart disease is a common feature,

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as is growth retardation, partially because of spinal involvement and often in association with muscular atrophy. Early death is not a feature of the late infantile form. Vacuolated cells in blood smears and foam cells in bone marrow are present in all forms of galactosialidosis.

Wolman Disease Etiology

Wolman disease is caused by a deficiency of lysosomal acid lipase, which is an enzyme involved in cellular cholesterol homeostasis and responsible for hydrolysis of cholesterol esters and triglycerides. The result of enzyme deficiency is defective release of free cholesterol from lysosomes, which leads to upregulation of LDL receptors and 3-hydroxy-3-methylglutaryl-CoA reductase activity. De novo synthesis of cholesterol and activation of receptor-mediated endocytosis of LDL then occur, leading to further deposition of lipid in lysosomes. The result is the accumulation of cholesterol esters and triglycerides in most tissues of the body, including the liver, spleen, lymph nodes, heart, blood vessels, and brain. An extreme level of lipid storage occurs in cells of the small intestine, particularly in the mucosa. In addition, neurons of the myenteric plexus demonstrate a high level of storage, with evidence of neuronal cell death, which may account for the prominence of gastrointestinal (GI) symptoms (Wolman, 1995). Clinical Features

Clinical presentation of Wolman disease is within weeks of birth, with evidence of malnutrition and malabsorption, including symptoms of vomiting, diarrhea, steatorrhea, failure to thrive, abdominal distention, and hepatosplenomegaly. Adrenal calcifications may be seen on radiographs, and adrenal insufficiency appears. The presence of adrenal calcifications in association with hepatosplenomegaly and GI symptoms is strongly suggestive of Wolman disease. Later, mental deterioration becomes apparent. Laboratory findings include anemia secondary to foam cell infiltration of the bone marrow and evidence of adrenal insufficiency. The serum cholesterol level is normal. Death usually occurs before 1 year of age.

Infantile Sialic Acid Storage Disease

I-Cell Disease (Mucolipidosis Type II) Etiology

In normal cells, targeting of enzymes to lysosomes is mediated by receptors that bind a mannose 6-phosphate recognition marker on the enzyme. The recognition marker is synthesized in a two-step reaction in the Golgi complex. It is the enzyme that catalyzes the first step of this process, uridine diphosphate–N-acetylglucos­ amine:lysosomal enzyme N-acetylglucosaminyl-1-phosphotransferase, that is defective in I-cell disease. As a result, the enzymes lack the mannose 6-phosphate recognition signal, and the newly synthesized lysosomal enzymes are secreted into the extracellular matrix instead of being targeted to the lysosome. Consequently, multiple lysosomal enzymes are found in plasma at 10–20 times their normal concentrations. Affected cells, especially fibroblasts, show dense inclusions of storage material that probably consists of oligosaccharides, GAGs, and lipids; these are the inclusion bodies from which the disease name is derived. This disorder is found more frequently in Ashkenazi Jews, because of a putative founder effect. Clinical Features

I-cell disease can manifest itself at birth as coarse features, corneal clouding, organomegaly, hypotonia, and gingival hyperplasia. Birthweight and length are often below normal. Kyphoscoliosis, lumbar gibbus, and restricted joint movement are often present, and there may be hip dislocation, fractures, hernias, or bilateral talipes equinovarus. Dysostosis multiplex may be seen on radiographs. Severe psychomotor retardation, evident by 6 months of age, and progressive failure to thrive occur. The facial features become progressively coarser, with a high forehead, puffy eyelids, epicanthal folds, flat nasal bridge, anteverted nares, and macroglossia. Linear growth slows during the first year of life and halts completely thereafter. The skeletal involvement is also progressive, with development of increasing joint immobility and claw-hand deformities. Respiratory infections, otitis media, and cardiac involvement are common complications. Death usually occurs in the first decade of life because of cardiorespiratory complications.

Mucolipidosis Type IV Etiology

Infantile sialic acid storage disease is caused by a defective lysosomal sialic acid transporter that is responsible for efflux of sialic acid and other acidic monosaccharides from the lysosomal compartment. The defective transporter results in greater storage of free sialic acid and glucuronic acid within lysosomes and increased sialic acid excretion.

Although mucolipidosis type IV is associated with a partial deficiency of the lysosomal enzyme ganglioside sialidase, a deficiency of mucolipin 1, a member of the transient receptor potential mucolipin subfamily of channel proteins, is the cause of the disorder (Bargal et al., 2000; Sun et al., 2000). Mutations in the MCOLN1 gene result in lysosomal storage of lipids such as gangliosides, plus water-soluble materials such as GAGs and glycoproteins in cells from almost all tissues.

Clinical Features

Clinical Features

Etiology

Infantile sialic acid storage disease often manifests itself at birth as mildly coarse features, hepatosplenomegaly, ascites, hypopigmentation, and generalized hypotonia. Mild dysostosis multiplex may be seen on radiographs. Failure to thrive and severe mental and motor retardation soon appear. Cardiomegaly may be present. Corneas are clear, but albinoid fundi have been reported (Lemyre et al., 1999). Vacuolated cells are seen in a tissue biopsy sample, and electron microscopy demonstrates swollen lysosomes filled with finely granular material. CNS changes include myelin loss, axonal spheroids, gliosis, and neuronal storage. Death occurs in early childhood. Infantile sialic acid storage disease can also manifest itself as fetal ascites, nonimmune fetal hydrops, or infantile nephrotic syndrome (Lemyre et al., 1999).

The age of onset for mucolipidosis type IV ranges from infancy to 5 years. Presenting features include corneal clouding (may be congenital), retinal degeneration, blindness, hypotonia, and mental retardation. Survival of affected patients into the fourth decade of life has been reported (Chitayat et al., 1991). Cytoplasmic inclusions are noted in many cells, including those in conjunctiva, liver, and spleen, as well as fibroblasts.

Mucopolysaccharidosis Type VII (Sly Disease) Etiology

Sly disease is a member of a group of LSDs that are caused by a deficiency of enzymes catalyzing the stepwise degradation of GAGs. Skeletal and neurologic involvement are variable. There is a wide

CHAPTER 23  Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and SLOS Presenting in the Neonate

spectrum of clinical severity among the mucopolysaccharidoses and even within a single enzyme deficiency. Most of these disorders manifest themselves in childhood, but type VII is included in this chapter because of its well-recognized neonatal and infantile presentations. Sly disease is caused by β-glucuronidase deficiency and results in lysosomal accumulation of GAGs, including dermatan sulfate, heparan sulfate, and chondroitin sulfate, causing cell, tissue, and organ dysfunction. Clinical Features

Sly disease can manifest itself as a wide spectrum of severity. Patients with the early-onset or neonatal form may have coarse features, hepatosplenomegaly, moderate dysostosis multiplex, hernias, and nonprogressive mental retardation. Corneal clouding is variably present. Frequent episodes of pneumonia during the first year of life are common. Short stature becomes evident. Granulocytes have coarse metachromic granules. A severe neonatal form associated with hydrops fetalis and early death has been recognized frequently. Milder forms of the disease with later onset are also known.

Diagnosis, Management, and Prognosis Growing recognition of LSDs in the neonate has led to expansion of the spectrum of possible clinical presentations in the newborn period. Diagnostic tools and options for treatment also continue to advance. For example, newborn screening (NBS) for mucopolysaccharidoses has begun in several states, with the goal to offer treatment with enzyme infusion or hematopoietic stem cell transplantation (HSCT) for affected babies (Vogler et al., 1999; Hopkins et al., 2015). The state of New York has implemented NBS for Krabbe disease that uses dried blood spots. The test uses a tandem mass spectrometry–based enzyme analysis (Li et al., 2004a). This test has resulted in a fairly large number of positive newborn screens for Krabbe disease, most of which appear to be false positives, including enzyme perturbations that are not linked with clinical disease (Duffner et al., 2009). As a consequence, an expert advising panel, the Krabbe Consortium of New York State, has been generated to establish standardized clinical evaluation guidelines (Wasserstein et al., 2016). The goal is to help physicians determine which infant with a positive newborn screen may express disease and require treatment, such as HSCT in early infancy. The neonatologist is urged to work closely with appropriate experts to explore diagnostic and treatment protocols on an individual basis. Larger panels of multiplex testing for various other LSDs are in the testing stages (Li et al., 2004b), and some states in the United States are poised to begin implementing LSD NBS. Currently a federal advisory committee actively reviews and makes recommendations to the US Secretary of Health and Human Services about the introduction of new NBS tests in the United States, with the aim of vetting proposed tests for need, cost-effectiveness, and availability of effective and timely therapy. The Recommended Universal Screening Panel has added mucopolysaccharidosis type I to the list of diseases that ought to be screened in every state. Ross (2012) performed an ethical and policy analysis using the Wilson and Jungner criteria for public health screening and concluded that the data do not support the incorporation of screens for LSDs into NBS programs. Instead, they should entail institutional review board–approved research protocols that require parental consent. Recognizing LSDs in the newborn period can be difficult, because they often mimic more common causes of illness in newborns, such as respiratory distress, nonimmune hydrops fetalis, liver disease,

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and sepsis. The initial step in the diagnosis of these disorders is to consider them in the differential diagnosis of a sick or unusualappearing newborn. At times the phenotype may suggest a specific diagnosis, such as respiratory distress and painful, swollen joints in Farber lipogranulomatosis or GI symptoms, hepatosplenomegaly, and adrenal calcifications in Wolman disease. Subtle dysmorphic features, coarsening of features, and radiographic evidence of dysostosis multiplex are also strong indications that LSDs should be considered. Routine laboratory findings are often normal or nonspecific. Affected infants do not have episodes of acute metabolic decompensation. Anemia and thrombocytopenia may be seen because of bone marrow involvement. Vacuolated cells may be found in peripheral blood, but the absence of this finding does not exclude LSD. Elevated cerebrospinal fluid protein level is seen in Krabbe disease and Farber lipogranulomatosis type I. Nonimmune hydrops fetalis deserves special mention. The physician must consider LSDs as the cause of nonimmune hydrops fetalis or unexplained ascites in the affected newborn. The following LSDs are potential causes: sialidosis type II, mucopolysaccharidosis types VII and IV, infantile sialic acid storage disease, Salla disease, galactosialidosis, Gaucher disease type 2, GM1 gangliosidosis, I-cell disease, Niemann–Pick disease types A and C, Wolman disease, and Farber disease (Staretz-Chacham et al., 2009). The mechanisms of edema are unclear. Furthermore, not all of the 13 LSDs routinely appear in the neonatal period. Directed analysis of urine is helpful for conditions in which characteristic metabolites are excreted in urine. One- or twodimensional electrophoresis or thin-layer chromatography can detect excess excretion of urine GAGs, oligosaccharides, or free sialic acid, but all urinary tests for the diagnosis of LSDs can have falsenegative results. Examination of bone marrow or other tissues may demonstrate storage macrophages in Gaucher disease and in Niemann–Pick disease types A and C. Small skin or conjunctival biopsy specimens may demonstrate storage within lysosomes in most of these disorders. Definitive diagnosis for all LSDs, except for Niemann–Pick C disease, is confirmed by enzymatic assays in serum, leukocytes, fibroblasts, or a combination of these. The diagnosis of Niemann– Pick C disease requires measurement of cellular cholesterol esterification and documentation of a characteristic pattern of filipin–cholesterol staining in cultured fibroblasts during LDL uptake. Analysis of DNA mutations may be helpful for the diagnosis of Niemann–Pick C disease, Gaucher disease, and some other conditions, and it will become increasingly available for other conditions. An imperfect genotype–phenotype correlation impedes the use of mutation analysis as a prognostic tool. In addition, prenatal diagnosis is available for most LSDs through the use of enzyme assays performed on amniocytes or chorionic villus cells or measurements of levels of stored substrate in cultured cells or amniotic fluid. As mutation analysis becomes more prevalent, it will increasingly substitute for biochemical and enzymatic methods. These conditions must also be considered in the dying infant, and the neonatologist must be prepared to request the appropriate samples for diagnosis at the time of death. In surviving patients, treatment and management must be considered. All the LSDs are chronic and progressive conditions for which there is no curative treatment. Gene transfer therapy holds promise but is not currently available for LSDs. With few exceptions, current standard medical management is supportive and palliative. Patients must be continually reassessed for evidence of disease progression and associated complications. These complications manifest themselves at variable

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ages and can include hydrocephalus, valvular heart disease, joint limitation, and obstructive airway disease. For several disorders, particularly neonatal Gaucher disease and Niemann–Pick C disease, splenectomy may be indicated to relieve severe anemia and thrombocytopenia. This procedure enhances the risk of serious infections, and it can accelerate the progression of disease at other sites. Patients with Krabbe disease may have significant pain of radiculopathy and spasms, and alleviation of that pain is important for the patient’s comfort. The administration of a glutamic acid transaminase inhibitor, vigabatrin, has been used in a small number of patients with Krabbe disease, because part of the disease may involve a secondary deficiency of γ-aminobutyric acid (Barth, 1995). Low-dose morphine has also been reported to reduce the irritability associated with this disorder (Stewart et al., 2001). Enzyme replacement therapy (ERT) with imiglucerase (Cerezyme®, Sanofi Genzyme), a recombinant enzyme, is available for Gaucher disease. Although ERT has successfully reversed many of the systemic manifestations of the disease, it has been suggested that ERT should not be given to patients with Gaucher disease type 2 who already have severe neurologic signs, because no substantial relief has been demonstrated to occur in the neurologic symptoms of patients treated (Erikson et al., 1993; McCabe et al., 1996). ERT should be discussed with families, and in some instances it may be appropriate to provide ERT until it has been established that the patient does not have the less severe form of Gaucher disease type 3 (Weiss et al., 2015). HSCT has been tried for a variety of LSDs. The rationale for the procedure is that circulating blood cells derived from the transplanted marrow become a source of the missing enzyme. Results of HSCT in disorders of GAGs show that after successful engraftment, leukocyte and liver tissue enzyme activity normalizes, organomegaly decreases, and joint mobility increases. Skeletal abnormalities stabilize but do not abate. Whether brain function can be improved in patients with CNS disease remains questionable. Some patients maintain their learning capability or intelligence quotient, but others continue to deteriorate. Clinical experience and studies in animal models indicate that HSCT before the onset of neurologic symptoms can prevent or delay the occurrence of symptoms, whereas there is no clear benefit if transplantation is performed when symptoms are already present (Hoogerbrugge et al., 1995). HSCT in patients with nonneuropathic Gaucher disease can result in complete disappearance of all symptoms; however, the procedure is associated with significant risks (Hoogerbrugge et al., 1995) that must be balanced against lifelong ERT. Currently it is unclear to what extent patients with Gaucher disease type 2 would benefit from transplantation (Weiss et al., 2015); therefore it is generally not recommended. HSCT has also been attempted in a small number of patients with infantile Krabbe disease, Farber lipogranulomatosis, and Niemann–Pick A disease. The outcome after transplantation for these few patients has been poor, with continued disease progression and death. Success may depend on treatments started very early in life before the onset of neurologic signs of diseases (Escolar et al., 2005, 2006 ). Krivit et al. (2000) reported successful longterm bone marrow engraftment in a patient with Wolman disease that resulted in normalization of peripheral leukocyte lysosomal acid lipase enzyme activity. The patient’s diarrhea resolved; cholesterol, triglyceride, and liver function values normalized, and the patient attained developmental milestones. LSDs are not all equally amenable to HSCT, and the use of HSCT as a treatment modality for most LSDs remains uncertain. In a small number of cases,

HSCT has been performed in utero after prenatal diagnosis showing an affected fetus, and experimental protocols are available for families who wish to pursue this option. The preferred treatment to reduce the accumulation of storage material in intestine and phagocytes in lysosomal acid lipase deficiency is ERT (Burton et al., 2015; Rader 2015), and there is now a trial using sebelipase alfa to treat Wolman disease (www. ClinicalTrials.gov identifier NCT01757184).

Congenital Disorders of Glycosylation Etiology CDGs are a group of more than 100 genetic diseases that involve various defects in the process of modifying proteins, lipids, or other biomolecules with glycans (sugar molecules or chains) (Freeze et al., 2014). Glycosylation, the addition of glycans to biomolecules, is essential to many biologic processes, such as aiding with correct folding, protecting against premature destruction, directing intracellular localization and transport, and modifying the biologic function of these biomolecules. The first CDG discovered (PMM2-CDG) was described by Jaak Jaeken in 1980 and was initially termed carbohydrate-deficient glycoprotein syndrome because of abnormalities seen in multiple serum glycoproteins in the affected individuals (Jaeken et al., 1980; Jaeken et al., 1984). When several more human glycosylation disorders were identified, this group of disorders was renamed congenital disorders of glycosylation. The decision was made to designate the types of CDG into either a group I or a group II disorder on the basis of the transferrin pattern obtained by isoelectric focusing, with specific diagnoses alphabetized consecutively as they were identified (i.e., CDG Ia, Ib, Ic, IIa, IIb, etc.) (Aebi et al., 1999). Improved molecular diagnostics expanded the definition of CDGs to include genetic diseases that primarily disrupt the process of formation of any glycoconjugate (i.e., glycoproteins, glycolipids, glycosaminoglycan, etc.), resulting in an exponential growth of the number of pathways and individual disorders (Jaeken, 2010). In 2009 the nomenclature was updated, and currently specific CDG types are named starting with the affected gene symbol (not in italics) followed by CDG (e.g., CDG Ia is now PMM2-CDG) (Jaeken et al., 2009). It is estimated that approximately 2% (~400) of our genes encode proteins involved with the glycosylation process, which occurs in a variety of locations within the cell, including the cytosol, endoplasmic reticulum, and Golgi apparatus. The underlying mechanism for the clinical manifestations of most of these disorders is still unclear. Given the complexity of glycosylation, there are multiple methods to subdivide these disorders. One classification schema sorts CDGs into protein N-linked glycosylation defects, protein O-linked glycosylation defects, glycosylphosphatidylinositol (GPI) anchor glycosylation defects, lipid glycosylation defects, and defects in multiple glycosylation and other pathways (Jaeken, 2011). In this chapter we use this classification method to help organize our discussion of the CDGs that manifest themselves in the neonatal period.

Clinical Presentations Because so many biologic functions are dependent on the correct glycosylation, the phenotypic spectrum of CDG defects is extremely broad and ranges from mild to severe disease and from a single-organ system to multisystem disease. Clinical features alone are insufficient

CHAPTER 23  Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and SLOS Presenting in the Neonate

to define the CDG type. A CDG should be considered in any unexplained clinical condition, but especially in multiorgan disease with neurologic involvement (Table 23.2).

N-Linked Protein Glycosylation Defects Etiology

N-linked protein glycosylation, the process involved with attaching glycans to the asparagine residue of target proteins, was the first discovered and is the best understood glycosylation pathway in humans. Classically, these disorders were divided into two categories: type I, which results in defects in N-glycan assembly, and type II, which results from defects in N-glycan processing. The initial assembly steps of N-glycosylation occur on the endoplasmic reticulum membrane, where sugars are attached in a stepwise manner to dolichol phosphate to form a lipid-linked oligosaccharide. Sugars are donated by an activated nucleotide sugar (uridine diphosphateN-acetylglucosamine and guanosine diphosphate-mannose), with the attached nucleotide providing the necessary energy for the transfer of the sugar to the lipid-linked oligosaccharide. This oligosaccharide is then transferred to the nascent protein cotranslationally. Once the oligosaccharide chain has been transferred to the protein, further processing occurs. The oligosaccharide is then transported to the Golgi apparatus, where further processing occurs. Different types of CDGs have been found in affected individuals who have defective enzymes in individual steps of this complex pathway, including the enzymes that form the dolichol backbone, transfer single sugars to the growing chain, interconvert activated monosaccharides, and transfer the oligosaccharide from dolichol to protein (Hennet, 2012; Jaeken, 2012). Clinical Features

N-linked glycosylation defects encompass a large number of disorders. Taken together these several dozen disorders are typically multisystemic with significant neurologic involvement with the notable exception of MPI-CDG, in which development can be normal (Sparks and Krasnewich, 1993). The most common perinatal findings include hypotonia, nonspecific dysmorphic features (mostly without inverted nipples or abnormal fat pads), feeding problems with growth delay, hepatopathy with elevated levels of transaminases, and abnormal coagulation profiles. Discriminating findings include neonatal hemorrhages (including cerebral hemorrhage) and thrombotic events, strabismus, nystagmus and other ophthalmologic findings, neonatal seizures, and an abnormal thyroid function screening result (Funke et al., 2013). Transferrin glycosylation analysis previously performed by isoelectric profiling and now performed by mass spectrometry methods shows an abnormal glycosylation pattern in many, but not all, of these disorders. Three disorders warrant special mention. PMM2-CDG (CDG Ia) is the classic and most common presentation, and many other N-linked CDGs mirror its presentation. Most affected infants appear normal at birth. In infancy, patients with PMM2-CDG can exhibit dysmorphic features, strabismus, nystagmus, and feeding difficulties; subsequently patients may exhibit growth failure, hypotonia, lipocutaneous abnormalities (including prominent fat pads on the buttocks), coagulopathy with thrombosis and bleeding, pericardial effusion, and mild to moderate hepatomegaly and hepatopathy. Approximately 20% of patients die during the first year of life after a course of severe fluid imbalance and sometimes anasarca in response to infection or their underlying glycosylation disorder (Grunewald, 2009). Having survived infancy, patients with PMM2-CDG can live into their seventh and eighth decades. Later manifestations include retinitis pigmentosa or retinal

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degeneration, pericardial effusion, renal cysts, coagulopathy, strokelike episodes, thrombotic disease, cerebral and olivopontocerebellar hypoplasia, ataxia, peripheral neuropathy followed by lower extremity atrophy, and hypogonadism. In general, patients have an extroverted disposition and happy appearance (Krasnewich et al., 2007). MPI-CDG (CDG Ib) stands out in this group of disorders because patients with MPI-CDG can have normal development, and mannose is a known targeted therapy. These individuals can experience vomiting, protein-losing enteropathy, and progressive liver fibrosis (Jaeken and Matthijs, 2007) but can also survive to adulthood. NGLY1-CDDG is the first described disorder of N-linked deglycosylation. It presents with hepatopathy, alacrima (lack of tears), intellectual disability, and movement disorder. In infancy many times the first symptom is poor feeding and motor delay with hyperkinesis (Need et al., 2012).

O-Linked Protein Glycosylation Defects Etiology

O-glycosylation consists of attachment of a monosaccharide (mannose, fructose, or xylose) or the assembly of a glycan and its attachment to a serine or threonine residue of a target protein. O-glycosylation differs from N-glycosylation in that it does not occur at the same time as the protein is being translated but occurs posttranslationally, exclusively in the Golgi apparatus, without further processing (Jaeken and Matthijs, 2007). O-glycosylation can be classified according to the type of sugar that is attached to the serine or threonine. Examples of O-glycosylation include O-mannosylation, O-xylosylation, and O-fucosylation. Clinical Features

The clinical features differ significantly depending on which type of O-glycosylation is defective. Deficiency of O-N-acetylgalatosamine linkage can lead to familial tumoral calcinosis with phosphatemia and massive calcium deposits in the skin and subcutaneous tissues (Freeze and Schachter, 2009). A defect in O-fucosylation has been shown to lead to Peters plus syndrome characterized by anterior eye chamber defects, disproportionate short stature, developmental delay, and cleft lip and/or palate (Lesnik Oberstein et al., 2006). Defects in O-xylosylation will lead to defective anchoring of GAGs to proteins and thus impaired proteoglycan formation. Defective O-xylosylation can lead to progeroid-type Ehlers–Danlos syndrome characterized by failure to thrive, loose skin, skeletal abnormalities, hypotonia, and hypermobile joints. Defects in forming heparin sulfate, also attached to proteins via O-xylosylation, cause congenital exostosis, an autosomal dominant disorder where patients have bony outgrowths usually at the growth plate of the long bones. Defective cartilage proteoglycan sulfation leads to achondrogenesis, diastrophic dystrophy, and atelosteogenesis that manifest themselves as symptoms in cartilage and bone such as cleft palate and club feet and in the severest cases lead to perinatal death from respiratory insufficiency (Freeze and Schachter, 2009). Additionally, there are more than a dozen different genetic disorders that lead to a defect in O-mannosylation (Endo, 2015). O-mannosylation defects lead to hypoglycosylation of α-dystroglycan, an important glycoprotein needed to link the intracellular cytoskeleton of muscle to the extracellular matrix. These disorders, collectively referred to as α-dystroglycanopathies, have a wide spectrum of clinical severity and encompass previously described disorders, ranging from Walker–Warburg syndrome, muscle–eye– brain disease, and Fukuyama congenital muscular dystrophy to limb–girdle muscular dystrophy (Mercuri et al., 2009; Topaloglu, 2009). In the neonate, clinical features involve the triad of muscle,

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eye, and brain, and may include hypotonia; muscle weakness; microcornia; microphthalmia; pale, hypoplastic or absent optic nerves; colobomas; cataracts; iris hypoplasia; glaucoma; retinal dysplasia or detachment; and brain structural abnormalities, including hydrocephalus, brainstem hypoplasia, cerebellar cysts, cobblestone lissencephaly, polymicrogyria, cerebellar vermis and hemisphere atrophy, hypoplasia of the pyramidal tracts, and absence of the corpus callosum. There is no specific blood or urine biochemical marker available for this group of disorders. Elevated creatine kinase level is frequently noted. Muscle biopsy with specialized immunohistochemical staining may show deficient glycosylated α-dystroglycan and normal β-dystroglycan level. Molecular testing is needed to confirm the specific type (Sparks et al., 1993).

Combined Glycosylation Defects Etiology

Combined N-glycosylation and O-glycosylation and other glycosylation defects are important because they appear to affect trafficking in the glycosylation machinery (Grunewald, 2007). Several of these disorders involve defects in channels involved in activated sugar-nucleotide transport (SLCx-CDG). Some affect vesicular transport (COGx-CDG) in general. Others affect the process of sugar activation (attaching nucleotides to monosaccharides so that they can be used for glycosylation). Yet others cause abnormalities in the Golgi apparatus structure (TMEMx-CDG), which needs to be intact for glycosylation to proceed (Ungar et al., 2002). Clinical Features

In the neonate the most frequent presenting symptoms include neonatal microcephaly; neonatal seizures; strabismus; hypotonia; dysmorphic features, especially cutis laxa; feeding problems with growth delay; and hepatic involvement (Funke et al., 2013). Again, encompassing a very large group of disorders, the presentations are very heterogeneous and include not only multisystemic diseases with the aforementioned symptoms but also single system disorders such as congenital dyserythropoietic anemia type II due to SEC23B-CDG.

Glycosylphosphatidylinositol Anchor Glycosylation Defects Etiology

The biosynthesis and attachment of GPI anchors to proteins occur in the endoplasmic reticulum and Golgi apparatus and involve 11 steps and at least 27 genes (Kinoshita et al., 2008). To date, inherited loss-of-function mutations in more than a dozen of these genes have been implicated in human disease. GPI anchors are attached during posttranslational modification and allow these proteins to attach to the outer leaflet of the cell membrane and face the extracellular environment. This permits these proteins to participate in processes such as signal transduction and immune response (Paulick and Bertozzi, 2008; Ferguson et al., 2009). Clinical Features

Typically, individuals affected with GPI anchor disorders have a severe phenotype and present in infancy with epilepsy, intellectual disability, and multiple congenital anomalies, including heart, skeletal (especially abnormalities in phalanges), endocrine, ophthalmologic, and facial anomalies, with possible abnormalities in alkaline phosphatase levels depending on the specific diagnosis (Jezela-Stanek et al., 2016). Although there is no standard blood or urine biomarker, flow cytometry markers show promise to be effective biomarkers in many of these disorders (Freeze et al., 2012).

Lipid Glycosylation Defects To date, three disorders of lipid glycosylation have been described. SIAT9-CDG, also known as Amish infantile epilepsy, was the first identified and is caused by a defect of lactosylceramide α-2,3-sialyltransferase (GM3 synthase) (Jaeken, 2006). This enzyme catalyzes the initial step in the biosynthesis of most complex gangliosides from lactosylceramide (Jaeken and Matthijs, 2007). The defect causes accumulation of lactosylceramide associated with decreased levels of gangliosides (Jaeken, 2006). Individuals with this disorder present with infantile-onset epilepsy with developmental stagnation, blindness, poor feeding, vomiting, failure to thrive, later-onset “salt and pepper” macules, and variable survival (Boccuto et al., 2014). ST3GAL-CDG is a cause of West syndrome (Freeze et al., 2015). B4GALNT1-CDG, also known as spastic paraplegia 26, is also a defect in ganglioside biosynthesis. However, onset of symptoms including gait abnormalities and central and peripheral nervous system involvement typically occurs after the neonatal period, in the first 2 decades of life (Boukhris et al., 2013).

Diagnosis CDG should be considered in young infants with several of the following features: • Neurologic signs, including hypotonia, hyporeflexia, or seizures • Ophthalmic signs, including abnormal eye movements, cataracts, optic nerve atrophy, retinitis pigmentosa, or glaucoma • Hepatic and GI signs, including ascites or hydrops, hepatomegaly, diarrhea, and protein-losing enteropathy • Endocrinologic signs, including hyperinsulinemic hypoglycemia and hypothyroidism • Hematologic signs, including thrombosis or coagulopathy with factor deficiency • Signs of renal or cardiac disease • Musculoskeletal signs, including congenital muscular dystrophy, and congenital joint contractures • Dysmorphic features, microcephaly, or abnormal skin findings Serum transferrin isoform analysis is the most available screening method, but it detects only N-glycosylation and some mixed glycosylation defects. Until about 2000, transferrin screening was achieved by isoelectric focusing of transferrin; failure to correctly synthesize the N-linked glycans alters the charge on serum transferrin and consequently its migration in an electrophoretic field. Since then, however, mass spectrometry methods, capable of identifying individual oligosaccharides and complete glycans by mass and charge, have replaced transferrin isoelectric focusing as the standard method for screening patients for CDGs (Sturiale et al., 2011). Transferrin and glycan analysis may yield false positive results in galactosemia, inborn errors of fructose metabolism, alcohol consumption, certain bacterial (neuraminidase-producing) infections, and in cases of mutations in transferrin itself. False negatives can occur in the first 3 weeks of life (Freeze et al., 2012). There are also reported cases where initially abnormal transferrin glycosylation normalizes without relief of symptoms. There are also N-linked defects known to not show transferrin isoform abnormalities (MOGS-CDG, TUSC3-CDG, SLC35A1-CDG, SLC35C1-CDG) (He et al., 2012). Apolipoprotein CIII glycan analysis has been used in the screening of some mixed and O-glycosylation disorders. Urine oligosaccharide screening is useful in detecting MOGS-CDG. Many defects

CHAPTER 23  Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and SLOS Presenting in the Neonate

in GPI synthesis can be identified by flow cytometry of GPIanchored proteins, such as FLAER or CD59 on leukocytes. Not all subtypes of CDGs have convenient biochemical markers; for example, screening for congenital muscular dystrophies caused by defective O-mannosylation requires a muscle biopsy with the use of monoclonal antibodies directed against the glycan (He et al., 2012). There are also no simple markers for defects in GAG biosynthesis. Since the advent of next-generation sequencing and exome analysis, most CDGs have been diagnosed molecularly (Timal et al., 2012). Once variants are identified in the specific gene, if novel, the functional consequence of the mutation can be confirmed by enzymatic assays in peripheral blood leukocytes or cultured fibroblasts for PMM2-CDG and MPI-CDG and on a research basis for other types. Prenatal diagnosis is possible in all types of CDG for which the molecular defect is known (Grunewald, 2007). The vast majority of CDGs are autosomal recessive disorders; POGLUT1-CDG and POFUT1-CDG (Dowling–Degos disease), EXT1&2-CDG (hereditary multiple exostoses syndrome), and SEC63-CDG and PRKCSH-CDG (polycystic liver disease) are autosomal dominant; C1GALT1C1-CDG, PIGA-CDG, SSR4CDG, SLC35A2-CDG, ALG13-CDG, and MAGT1-CDG are X-linked.

Treatment, Management, and Prognosis A specific treatment is available for only a minority of CDGs. MPI-CDG can be treated with orally administered mannose (Thiel and Korner, 2013), which can help significantly with the proteinlosing enteropathy but does not necessarily halt the progression of the liver disease. Heparin has also been used for protein-losing enteropathy in MPI-CDG (de Lonlay and Seta, 2009). In SLC35C1CDG, some patients respond to oral fucose supplementation; this treatment is effective only with regard to the typical recurrent infections with hyperleukocytosis and does not correct the neurodevelopmental aspects (Marquardt et al., 1999). In PIGM-CDG, butyrate has been shown to control the seizures in some cases (Almeida et al., 2007). There are ongoing trials to assess the efficacy of galactose in PGM1-CDG, and preliminary findings show promise that this therapy may alleviate the hypoglycemia, coagulopathy, and endocrinopathy seen in this disorder (Morava, 2014). The treatment and management of other types of CDGs are primarily supportive and palliative. In infancy, evidence of multisystem involvement and the resulting complications must be treated promptly. There is substantial mortality in the first years of life because of severe infection or vital organ failure (Jaeken, 2006; Grunewald, 2007).

Peroxisomal Disorders Peroxisomes are small, evolutionarily conserved, single membrane– bound cellular organelles that contain no internal structure or DNA and are characterized by an electron-dense core and a homogeneous matrix. Peroxisomes are found in all cells and tissues except mature erythrocytes and are in highest concentration in the liver and kidneys. They are formed predominantly by growth and division of preexisting peroxisomes, but they can also arise de novo from peroxisomal vesicles that originate from specialized compartments of the endoplasmic reticulum (Waterham and Ebberink, 2012; Braverman et al., 2016; Waterham et al., 2016). Their half-life is 1.5–2 days before they are randomly destroyed by autophagy. All peroxisomal proteins are encoded by nuclear genes, synthesized in cytosol, and imported posttranslationally

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into the peroxisome (Waterham and Ebberink, 2012). The import of proteins into the peroxisome is mediated by specific targeting sequences known as peroxisomal targeting sequences (Waterham et al., 2016). Peroxisomes contain enzymes that use oxygen to oxidize a variety of substrates, thereby forming peroxide. The peroxide is decomposed within the organelle by the enzyme catalase to water. This process protects the cell against peroxide damage through compartmentalization of peroxide metabolism within the organelle. Peroxisomes can also function to dispose of excess reducing equivalents and may contribute to thermogenesis, producing heat from cellular respiration (Gould et al., 2001). More than 70 enzymes have been found within peroxisomes (Braverman et al., 2016). The proteins have multiple functions, both synthetic and degradative (Braverman et al., 2016; Waterham et al., 2016). The primary synthetic functions are plasmalogen synthesis and bile acid and docosahexanoic acid formation. Plasmalogens constitute 5%–20% of phospholipids in cell membranes and 80%–90% of phospholipids in myelin. They are involved in platelet activation and may also protect cells against oxidative stress. Degradative functions include (1) β-oxidation of very long chain fatty acids (VLCFAs) (≥C23), fatty acids (down to C8 to C6), long-chain dicarboxylic acids, prostaglandins, and polyunsaturated fatty acids; (2) oxidation of bile acid intermediates, pipecolic acid and glutaric acid (intermediates in lysine metabolism), and phytanic acid; (3) deamination of D-amino acids and L-amino acids; (4) metabolism of glycolate to glyoxylate; (5) polyamine degradation (spermine and spermidine); and (6) ethanol clearance. At least 16 conditions caused by peroxisomal enzyme deficiencies have been confirmed (Klouwer et al., 2015; Braverman et al., 2016; Waterham et al., 2016). Peroxisomal disorders constitute a clinically and biochemically heterogeneous group of inherited diseases that result from the absence or dysfunction of one or more peroxisomal enzymes. Disorders in which more than one enzyme is affected are collectively termed peroxisomal biogenesis disorders (PBDs). Disorders in which only one enzyme is affected encompass the remaining known disorders. All but one are inherited in an autosomal recessive manner. The pathophysiologic features apparently involve either deficiency of necessary products of peroxisomal metabolism or excess of unmetabolized substrates. Disorders with similar biochemical defects may have markedly different clinical features, and disorders with similar clinical features may be associated with different biochemical findings. General features of peroxisomal disorders, each of which can be evident in the newborn period, are as follows: • Dysmorphic craniofacial features • Neurologic dysfunction, primarily consisting of severe hypotonia, possibly associated with hypertonia of extremities, seizures, and abnormalities in neuronal migration • Hepatodigestive dysfunction, including hepatomegaly, cholestasis, prolonged hyperbilirubinemia, and feeding difficulties • Rhizomelic shortening of the limbs, stippled calcifications of epiphyses, and renal cysts In this section we discuss the peroxisomal disorders that can manifest themselves in the newborn period.

Disorders of Peroxisomal Biogenesis Conditions in which multiple peroxisomal enzymes are affected can result from a disturbance of biogenesis of the organelle. Peroxisomal assembly includes matrix protein import, synthesis of new organelles, and fusion of existing organelles. The coordinated

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activity of 16 PEX proteins, or peroxins, encoded by their corresponding genes is required for this process (Braverman et al., 2013). The PEX genes responsible for disease in most human patients are known, with more than 60% of patients with PBD having mutations in PEX1; the second most commonly involved gene is PEX6 (Waterham et al., 2012; Braverman et al., 2013; Braverman et al., 2016). The overall incidence of PBD is estimated to be approximately 1 in 50,000 newborns (Klouwer et al., 2015; Braverman et al., 2016). Zellweger syndrome is the prototype of neonatal peroxisomal disease. It is a disorder of peroxisome biogenesis caused by failure to import newly synthesized peroxisomal proteins into the peroxisome. The proteins remain in the cytosol, where they are rapidly degraded. In this condition, peroxisomes are absent from liver hepatocytes or exist as “ghosts.” Neonatal adrenoleukodystrophy and infantile Refsum disease are also disorders of peroxisome biogenesis in which, as in Zellweger syndrome, disruption of function of more than one peroxisomal enzyme is demonstrable. A few residual peroxisomes, however, may be seen in the liver. These disorders represent a continuum of clinical severity, and the term Zellweger spectrum disorders (ZSDs) is now suggested (Braverman et al., 2013; Braverman et al., 2016). Features common across the spectrum include liver disease, variable neurologic dysfunction, developmental delay, retinopathy, neurosensory hearing loss, and adrenocortical dysfunction (Poll-The and Gärtner, 2012; Klouwer et al., 2015). Rhizomelic chondrodysplasia punctata, types 1 and 5, are caused by a defect in a subset of peroxisomal enzymes resulting from mutations in the PEX7 gene and the PEX5L isoform respectively. In these disorders, liver peroxisomes are demonstrable and normal in number, but their distribution and structure are abnormal. A new category of disorders, referred to as peroxisomal fission defects, has also been recognized. Peroxisomal fission defects are disorders caused by defects in proteins known to be involved with the proliferation and division of peroxisomes (Mff, Fisl, PEX11, DLP1) (Waterham et al., 2007; Schrader et al., 2012; Waterham and Ebberink, 2012; Waterham et al., 2016). Finally, Heimler syndrome, a rare recessive disorder, typically presenting in young childhood with sensorineural hearing loss, amelogenesis imperfecta, nail abnormalities, and retinal pigmentation, was recognized as a mild PBD disorder involving mutations in PEX1 and PEX6 (Ratbi et al., 2015).

Zellweger Syndrome Zellweger syndrome is most often evident at birth, with affected newborns having dysmorphic facial features including large fontanels, high forehead, flat occiput, epicanthus, hypertelorism, upward-slanting palpebral fissures, hypoplastic supraorbital ridges, abnormal ears, severe weakness and hypotonia, hepatomegaly, multicystic kidneys, and congenital heart disease. Seizures, feeding difficulties, and postnatal growth failure soon manifest themselves. Ophthalmologic examination may detect cataracts, corneal clouding, glaucoma, optic atrophy, retinitis pigmentosa, and Brushfield spots. Somatic sensory evoked responses and electroretinograms are abnormal. Hearing assessment often shows an abnormal brainstem auditory evoked response consistent with sensorineural hearing loss. Skeletal radiographs demonstrate epiphyseal stippling, and cranial imaging shows leukodystrophy and neuronal migration abnormalities. Hepatic cirrhosis and severe psychomotor retardation occur later. Laboratory analysis may demonstrate abnormal liver function values, hyperbilirubinemia, or hypoprothrombinemia. Death usually occurs within the first year of life, the average life span being 12.5 weeks.

Neonatal Adrenoleukodystrophy Clinically, neonatal adrenoleukodystrophy is similar to, but less severe than, Zellweger syndrome. Differences include less dysmorphology, absence of chondrodysplasia punctata and renal cysts, and fewer neuronal and gray matter changes. Patients with neonatal adrenoleukodystrophy may have striking white matter disease, however, and often show degenerative changes in adrenal glands. They also have slow psychomotor development followed by neurodegeneration that usually begins before the end of the first year of life. Disease progression is slower than that observed in Zellweger syndrome, and longer survival is usual, to an average of approximately 15 months of age or into the teen years (Waterham et al., 2016). Infantile Refsum Disease Patients with infantile Refsum disease also have relatively mild dysmorphic features, such as epicanthic folds, midface hypoplasia with low-set ears, and mild hypotonia. Early neurodevelopment is normal, possibly up to 6 months of age, but then slow deterioration begins. Later, sensorineural hearing loss (100%), anosmia, retinitis pigmentosa, hepatomegaly with impaired function, and severe cognitive impairment are evident. Patients learn to walk, although their gait may be ataxic and broad based. Diarrhea and failure to thrive may also be seen. Chondrodysplasia punctata and renal cysts are absent. Neuronal migration defects are minor and adrenal hypoplasia occurs. The life span of patients with infantile Refsum disease ranges from 3 to 11 years or into adulthood. Rhizomelic Chondrodysplasia Punctata Patients with defects in the biosynthesis of ether phospholipids present with rhizomelic chondrodysplasia punctata. Five genetically distinct, but clinically indistinguishable, groups exist, three of which are single enzyme defects (types 2, 3, and 4) and the other two of which are peroxisomal biogenesis defects (types 1 and 5) (Waterham et al., 2016). Patients with rhizomelic chondrodysplasia punctata at birth have facial dysmorphia, microcephaly, cataracts, rhizomelic shortening of extremities with prominent stippling, and coronal clefting of vertebral bodies. The chondrodysplasia punctata is more widespread than in Zellweger syndrome and may involve extraskeletal tissues. Infants with this disorder have severe psychomotor retardation from birth onward and severe failure to thrive. In addition, patients may have joint contractures, and 25% experience ichthyosis. Neuronal migration is normal. The life span is usually less than 1 year. Peroxisomal Fission Defects The first described patient with a peroxisomal fission defect was a severely affected female patient with mitochondrial encephalopathy who died at 1 month of age (Waterham et al., 2007). She was noted to have microcephaly, mild dysmorphic features, truncal hypotonia, absent deep tendon reflexes, optic atrophy, failure to thrive, abnormal brain development, and severe developmental delay. She had elevated peripheral and central lactic acid and alanine levels, mildly elevated VLCFA levels, and abnormal-appearing peroxisomes and mitochondria in fibroblasts but normal oxidative phosphorylation values in fibroblasts and skeletal muscle specimens (Waterham et al., 2007). Evaluation revealed a peroxisomal and mitochondrial fission defect with a heterozygous, dominant-negative mutation in the dynamin-like protein 1 gene (DLP1) (Waterham et al., 2007). Additional patients with DLP1 mutations have been described (Vanstone et al., 2016; Chao et al., 2016; Sheffer et al.,

CHAPTER 23  Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and SLOS Presenting in the Neonate

2016). Patients may not show significant peroxisomal or biochemical abnormalities.

Single Peroxisomal Enzyme Defects Of patients with suspected ZSD and elevated VLCFA levels, approximately 10%–15% will have a single enzyme defect (Braverman et al., 2013; Braverman et al., 2016). To date, three childhood disorders of peroxisomal fatty acid β-oxidation have been defined: D-bifunctional protein deficiency, acyl-CoA oxidase deficiency, and 2-methylacyl-CoA racemase deficiency (Waterham et al., 2016). The clinical presentation resembles that of biogenesis disorders. Previously, an isolated case of a fourth disorder, peroxisomal thiolase deficiency, was described (Goldfischer et al., 1986). On reinvestigation, however, this case was identified as D-bifunctional protein deficiency (Ferdinandusse et al., 2002).

D-Bifunctional Protein Deficiency D-bifunctional protein deficiency is a rare single peroxisomal enzyme defect that results in a phenotype similar to Zellweger syndrome. It is caused by mutations in the HSD17B4 gene encoding 17β-estradiol dehydrogenase, an enzyme involved in β-oxidation of VLCFAs and branched-chain fatty acids, including pristanic acid and bile acid intermediates, resulting in accumulation of VLCFAs, pristanic acid, and dihydroxycholestanoic acid and trihydroxycholestanoic acid (Shimozawa et al., 2011; Waterham et al., 2016). In general, children have severe CNS involvement consisting of profound hypotonia, uncontrolled seizures, and failure to acquire any significant developmental milestones. Children are usually born at term without evidence of intrauterine growth restriction. Dysmorphic features, similar to those seen in Zellweger syndrome, are notable in most children. In most cases, neuronal migration is disturbed, with areas of polymicrogyria and heterotopic neurons in the cerebrum and cerebellum. Death generally occurs before 1 year of age, but survival to at least 3 years of age is possible. Acyl Coenzyme A Oxidase Deficiency Acyl-CoA oxidase deficiency, also called pseudoneonatal adrenoleukodystrophy, is a rare, neuroinflammatory, neurodegenerative disorder (El Hajj et al., 2012; Wang et al.; 2015). It is caused by mutations in ACOX1 exclusively involved in the β-oxidation of straight-chain fatty acids resulting in the accumulation of VLCFAs (El Hajj et al., 2012; Waterham et al., 2016). Patients exhibit global hypotonia, deafness, and delayed developmental milestones with or without facial dysmorphic features. Patients may demonstrate early developmental skills but then show regression of skills typically between 24 and 48 months of age (Wang et al., 2015). Retinopathy with extinguished electroretinograms, nystagmus, optic atrophy, failure to thrive, hepatomegaly, areflexia, seizures, and white matter demyelination have also been reported (Poll-The et al., 1988; Carrozzo et al., 2008; El Hajj et al., 2012). 2-Methylacyl Coenzyme A Racemase Deficiency 2-Methylacyl-CoA racemase (AMACR) deficiency is a rare disorder caused by mutations in the AMACR gene encoding the enzyme 2-methylacyl-CoA racemase. The enzyme catalyzes the isomerization of fatty acids with a methyl group in the R configuration to the corresponding S configuration, an obligatory reaction in the steps leading to peroxisomal β-oxidation. This results in impaired bile acid synthesis and pristanic acid metabolism and subsequent accumulation of pristanic acid, (25R)-trihydroxycholestanoic acid, and (25R)-dihydroxycholestanoic acid (Setchell et al., 2003). Most

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patients present with an adult-onset ataxia and sensory neuropathy; however, an infantile presentation with cholestatic liver disease, coagulopathy, and fat-soluble vitamin deficiency has been reported (Setchell et al., 2003; Waterham et al., 2016).

X-Linked Adrenoleukodystrophy X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, with an estimated incidence of 1 in 17,000 (Waterham et al., 2016). It is caused by the altered function of the membrane-bound protein ABCD1, which predominantly catalyzes the import of straight-chain VLCFAs into peroxisomes (Waterham et al., 2016). It does not usually present in the newborn period; however, contiguous ABCD1 DXS1357E deletion syndrome, caused by a contiguous gene deletion of ABCD1 and its upstream gene DXS1357E, may. Four male patients have been reported with profound neonatal hypotonia, severe growth and developmental retardation, cholestatic liver disease, accumulation of VLCFAs, and death within the first year of life (Corzo et al., 2002; Shimozawa et al., 2011; Iwasa et al., 2013).

Diagnosis, Management, and Prognosis The key to diagnosing peroxisomal disorders is a high index of suspicion. Peroxisomal disorders should be considered in newborns with dysmorphic facial features, skeletal abnormalities, shortened proximal limbs, neurologic abnormalities (including hypotonia or hypertonia), ocular abnormalities, and hepatic and renal abnormalities. Babies with abnormal vision, hearing, or somatosensory evoked potentials should also be considered for these diagnoses. Peroxisomal disorders are not associated with acute metabolic derangements or abnormal routine laboratory test findings. Measurements of the levels of VLCFAs, phytanic acid, pristanic acid, pipecolic acid, bile acid intermediates, and plasmalogens are required for diagnosis. Zellweger syndrome is associated with elevations of the levels of VLCFAs, phytanic acid, pipecolic acid, and bile acid intermediates and a decrease in plasmalogen synthesis. Neonatal adrenoleukodystrophy and infantile Refsum disease have similar biochemical findings; however, the defect in plasmalogen synthesis and the degree of VLCFA accumulation are less severe. Laboratory findings in rhizomelic chondrodysplasia punctata include elevations of the levels of phytanic and pipecolic acids, a decrease in the levels of plasmalogens, and normal levels of VLCFAs and bile acid intermediates. Therefore screening that uses only levels of VLCFAs fails to detect rhizomelic chondrodysplasia punctata. Also, a small number of patients with mutations in PEX genes have been identified with mild or absent elevations in VLCFA levels (Braverman et al., 2016). D-bifunctional protein deficiency is associated with deficient oxidation of C23:0 and pristanic acid, leading to elevations of the levels of pristanic acid and, to a lesser extent, phytanic acid. This deficiency results in an elevated pristanic acid to phytanic acid ratio, which is generally not elevated in PBD. Abnormal VLCFA levels and elevations of the levels of varanic acid, an intermediate metabolite in β-oxidation, are also seen. Accumulation of bile acid intermediates is a variable finding. Abnormalities in the levels of phytanic acid and plasmalogens are age dependent. The elevation of the levels of phytanic and pristanic acids might not be demonstrable in newborns not consuming dairy products or other dietary sources of these fatty acids, and reduction in red blood cell plasmalogen levels may not be evident in children older than 20 weeks (Gould et al., 2001; Lee and Raymond, 2013; Braverman et al., 2016). Pipecolic acid levels are more likely to be abnormal in the urine of newborns and more

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abnormal in plasma at later ages (Braverman et al., 2016). A ketogenic diet may elevate VLCFA levels (Lee and Raymond, 2013; Braverman et al., 2016). A liver biopsy may be a useful adjunct diagnostic tool to assess the presence or absence and structure of peroxisomes. Definitive diagnosis for all types may require cultured skin fibroblasts for measurement of the levels of VLCFAs and their β-oxidation and, as needed, assay of the peroxisomal steps of plasmalogen synthesis, phytanic acid oxidation, subcellular localization of catalase, enzyme assays, and immunocytochemistry studies. More recently, however, next-generation sequencing panels for the PEX genes are being used for confirmatory diagnostic testing (Braverman et al., 2016). DNA study for deletions also has a role in diagnostic evaluation in some cases as demonstrated by the neonatal presentation of cases with deletion of the ABCD1 gene on the X chromosome (Corzo et al., 2002; Shimozawa et al., 2011; Iwasa et al., 2013). Diagnostic flow diagrams have been published by Shimozawa et al. (2011) and Klouwer et al. (2015). Prenatal diagnosis with a variety of methods is available. It can be accomplished in the first or second trimester by biochemical or genetic testing in chorionic villi cells or cultured amniocytes (Waterham and Ebberink, 2012; Klouwer et al., 2015; Braverman et al., 2016). Preimplantation genetic diagnosis can be performed when the PEX mutations are known. Carriers cannot be identified by biochemical testing (Waterham and Ebberink, 2012). One of the more interesting recent developments in peroxisomal disease is consideration of NBS. The combination of liquid chromatography and tandem mass spectrometry to detect elevated levels of VLCFAs (C26:0-lysophosphatidylcholine) in newborn dried blood spots has been validated as a diagnostic approach for X-ALD (Braverman et al., 2016). Legislation for X-ALD screening has passed in several states. Screening for X-ALD has recently been approved for addition to the Recommended Uniform Screening Panel. NBS for X-ALD should also detect the majority of ZSDs, permitting early diagnosis and intervention (Klouwer et al., 2015; Braverman et al., 2016). The prognosis for patients with a neonatal-onset peroxisomal disease remains poor, and patients frequently die within the first year of life (Klouwer et al., 2015). Patients with later presentation have a better prognosis but still have progressive disease. Plasma levels of metabolites do not correlate well with disease severity (Klouwer et al., 2015). There is, however, a generally good correlation between the defective PEX gene, the type of mutation, and the impact on peroxisomal assembly and function and the clinical severity (Waterham and Ebberink, 2012). Treatment for all peroxisomal disorders in the newborn period remains symptomatic and supportive. These disorders are chronic, progressive diseases with no currently available curative therapy. In patients with severe disease, seizure control, feeding, and respiratory support are the main focus of management (Braverman et al., 2016). Feeding difficulties, including malabsorption, are prominent and may require the use of elemental formulas and/or gastrostomy tube placement. Dietary reduction in VLCFAs has not been shown to reduce plasma VLCFA levels as most VLCFAs are produced endogenously (Braverman et al., 2016). In patients with X-ALD, dietary reduction of VLCFAs in combination with supplementation with Lorenzo’s oil (a 4 : 1 mixture of glyceryl trioleate and glyceryl trierucate) can reduce plasma VLCFA levels but does not affect progression of already present leukodystrophy (Braverman et al., 2016). Use of Lorenzo’s oil has not been studied in ZSDs but may be contraindicated because of the presence of increased levels of dietary monounsaturated fatty acids in patients who already accumulate large amounts of C26:1 (Klouwer et al., 2015;

Braverman et al., 2016). Because of impaired synthesis of docosahexanoic acid, supplementation with docosahexanoic acid was previously recommended. A placebo-controlled study, however, showed no clinical benefit with supplementation (Parker et al., 2010). Also, because of defective bile acid synthesis, supplementation with the fat-soluble vitamins, A, D, E, and K, is recommended (Braverman et al., 2016). Studies evaluating the effectiveness of bile acid supplementation (cholic acid and chenodeoxycholic acid) are limited, but bile acid supplementation may improve liver function especially in AMACR deficiency (Setchell et al., 2003; Braverman et al., 2016). Further supportive care includes use of antiepileptic medications for seizure control, oxygen supplementation as needed for respiratory difficulties, use of hearing aids or cochlear implants for hearing loss, use of glasses for vision difficulties, routine dental care, and routine immunizations. Screening for adrenal insufficiency should occur regularly, and replacement therapy should be started as indicated with stress doses when necessary. Citrate therapy may help prevent renal oxalate stones. Bone density and vitamin D status should be monitored. Comprehensive developmental services should be provided. Treatment guidelines have recently been proposed and published by Braverman et al. (2016). More recently, betaine and arginine have been recognized to be molecular chaperones that can improve peroxisomal assembly and may have a future therapeutic role (Waterham and Ebberink, 2012). HSCT is the established therapy for the cerebral childhood form of X-ALD, but there are no reports describing HSCT in ZSDs (Klouwer et al., 2015). Use of HSCT was recently reported in a young child with acyl-CoA oxidase deficiency. It was considered as a possible disease-arresting therapeutic intervention following recognition that the neuropathologic features of acyl-CoA oxidase deficiency resemble those of X-ALD (Wang et al., 2015). Despite full engraftment, the child experienced neurodegeneration and died in childhood (Wang et al., 2015). Hepatocyte transplantation and orthotopic liver transplantation have been described in patients with infantile Refsum disease with improvement in biochemical parameters and clinical course (Sokal et al., 2003; Van Maldergem et al., 2005). Gene therapy may provide future hope.

Smith–Lemli–Opitz Syndrome Etiology SLOS is a well-recognized autosomal recessive malformation syndrome, with an estimated incidence ranging from 1 in 10,000 to 1 in 70,000 in various populations (Smith et al., 1964; Porter, 2008; Cross et al., 2015). In 1993 it was discovered that SLOS is caused by a defect in cholesterol biosynthesis that results in low levels of cholesterol and elevated levels of 7-dehydrocholesterol (7DHC) and its isomer 8-dehydrocholesterol (8DHC) (Irons et al., 1993; Tint et al., 1994). Patients have markedly reduced activity of 7DHC reductase (Honda et al., 1995), the enzyme responsible for conversion of 7DHC to cholesterol encoded by the gene DHCR7 (Wassif et al., 1998). The cause of the clinical phenotype of SLOS may be related to deficient cholesterol, deficient total sterols, and toxic effects of either 7DHC or compounds derived from it, or a combination of these factors (Bianconi et al., 2015). Cholesterol is a major lipid component of cellular membranes such as myelin, and it is an important structural component of lipid rafts, which play a major role in intracellular signaling. In animal and in vitro models of SLOS, altered ratios of cholesterol, its dehydrocholesterol precursors, and its derivatives have been

CHAPTER 23  Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and SLOS Presenting in the Neonate

noted to alter membrane rigidity, alter electrostatic properties of biologic membranes that can change the activity of ion-dependent adenosine triphosphatases and channels, decrease the stability of lipid rafts leading to increases in degranulation of mast cells, and reduce ligand binding to receptors such as the serotonin 1A receptor. In addition, bile acids, steroid hormones, neuroactive steroids, and oxysterols are all synthesized from cholesterol, and dehydrocholesterols can also serve as precursors of related steroids, bile acids, and oxysterols that may be antagonists or agonists of the ones derived from cholesterol (Bianconi et al., 2015). Cholesterol is also involved in hedgehog signaling by acting as a cofactor and covalent adduct to hedgehog members (Cooper et al., 2003). Hedgehog is a family of signaling proteins that are critical to pattern formation through interactions with the homeobox genes during embryonic development, and altered hedgehog signaling could explain some malformations seen in SLOS, such as holoprosencephaly and postaxial polydactyly (Farese and Herz, 1998; Kelley and Hennekam, 2000; Cooper et al., 2003). Recently, attention has been drawn to the high sensitivity of 7DHC to oxidation, and thus increased free radical generation may be a possible contributor to certain aspects of the disease, such as retinal degeneration (Chang et al., 2014; Xu and Porter, 2015).

Clinical Features Recognition of the biochemical defect in SLOS provided the diagnostic test required to recognize the mildest and severest cases, substantially expanding the clinical spectrum of the condition. Classic SLOS is often evident at or before birth; affected patients have prenatal and postnatal growth retardation, microcephaly, and facial dysmorphism, including bitemporal narrowing, ptosis, epicanthic folds, anteverted nares, broad nasal tip, prominent lateral palatine ridges, retromicrognathia, and low-set ears. Other features include two- or three-toe syndactyly (found in 95% of patients), small proximally placed thumbs, occasionally postaxial polydactyly, and cataracts. Males usually have hypospadias, cryptorchidism, and a hypoplastic scrotum but may have ambiguous or female genitalia. Females may have a bicornuate uterus and/or septate vagina. Pyloric stenosis, cleft palate, bifid uvula, pancreatic anomalies, constipation, Hirschsprung disease, renal anomalies, congenital heart defects, and lung segmentation defects have also been reported. Hypotonia progressing to hypertonia is also present. Feeding difficulties and vomiting are common problems in infancy. Irritable behavior and shrill screaming may also pose problems during infancy. Older children frequently have hyperactivity, self-injurious behavior, sleep difficulties, and autistic characteristics. Cranial imaging studies and autopsies show defects in brain morphogenesis, including holoprosencephaly, frontal lobes, cerebellum, and brainstem hypoplasia, irregular gyral patterns, and irregular neuronal organization (Nowaczyk, 1993; Bianconi et al., 2015). Historically, approximately 20% of patients die within the first year of life, although others may survive for more than 30 years. The clinical severity in SLOS correlates best with either reduction in absolute cholesterol levels or the sum of 7DHC and 8DHC levels expressed as a fraction of total sterol levels (Waterham and Clayton, 2006). Life expectancy appears to correlate inversely with the number and severity of organ defects and with the kinds and numbers of limb, facial, and genital abnormalities (Tint et al., 1995). Developmental outcomes are also highly variable, ranging from severe mental retardation to normal intelligence. Growth is typically lower than in unaffected individuals, and specific growth charts have been developed (Lee et al., 2012). In adults, depression

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and anxiety may manifest themselves, and there has at least been one mildly affected female who has undergone a pregnancy with a good outcome (Ellingson et al., 2014). Testing for SLOS has been suggested for all patients with idiopathic intellectual impairment, behavioral anomalies, or both when associated with nonfamilial two- and three-toe syndactyly and failure to thrive (Jezela-Stanek et al., 2008).

Diagnosis The diagnosis of SLOS is based on findings of elevated levels of 7DHC and 8DHC. False-positive elevations of 7DHC levels occur in patients taking psychoactive medications such as aripiprazole, trazodone, and haloperidol and in patients with increased cholesterol synthesis because of bile acid loss after ileal resection (Bianconi et al., 2015). Plasma cholesterol levels are usually low, but cholesterol is a poor diagnostic marker since as many as 10% of patients at all ages have normal cholesterol levels. Also, in many laboratories, measured cholesterol levels include cholesterol as well as 7DHC and 8DHC (Kelley and Hennekam, 2000). Confirmation of diagnosis through molecular analysis of DHCR7 is possible and recommended in cases where the serum concentration of 7DHC is difficult to interpret or prenatal or preimplantation genetic diagnosis is desired. Patients with two null mutations or with mutations in putative loop 8 or 9 have a severer phenotype, and patients with two missense mutations seem to be more mildly affected. However, patients with the same genotype can have markedly different severity (Waterham and Hennekam, 2012). Modifier genes are likely present, and maternal APOE and ABCA1 genotypes that alter maternoplacental cholesterol transfer appear to modify disease severity (Witsch-Baumgartner et al., 2004; Lanthaler et al., 2013). If the genotype is unknown but prenatal testing is desired, abnormal levels of 7DHC from amniotic fluid or tissue from chorionic villus samples can be used for prenatal diagnosis, although false negatives can occur in mild cases. Prenatal sonographic findings of intrauterine growth retardation, increased nuchal translucency, nonimmune hydrops, unusual facial features, cystic hygroma, or major malformations in brain, heart, kidneys, limbs, genitalia, and palate are consistent with SLOS but have low sensitivity and specificity. Maternal serum screening showing low levels of unconjugated estriol, human chorionic gonadotropin, and alpha fetoprotein is also consistent with SLOS (Nowaczyk, 1993).

Treatment Because of the underlying biochemical defect in SLOS, targeted treatment strategies to date have mainly focused on supplying exogenous cholesterol with the goal of raising cholesterol levels and secondarily lowering 7DHC and 8DHC levels by downregulating the patient’s endogenous cholesterol synthesis. Cholesterol is typically given as a dietary modification (egg yolk, breast milk in infants), as a crystalline cholesterol suspension, or as a microencapsulated cholesterol powder with dosing dependent on the formulation ranging from 20 to 300 mg/kg (Irons et al., 1997; Kelley and Hennekam, 2000; Lin et al., 2005). Unfortunately dietary studies on cholesterol supplementation have not been conducted in a randomized fashion except for one short-term study that found no difference in short-term behavior in patients treated with cholesterol supplementation (Tierney et al., 2010). Case series have reported that cholesterol supplementation in SLOS has improved growth, development, and behavior, increased

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nerve conduction velocity, and decreased skin photosensitivity, susceptibility to infection, and cholestatic liver disease of infancy when used with and without bile acid replacement. Cholesterol supplementation in SLOS has minimal side effects (Nowaczyk, 1993; Bianconi et al., 2015). However, given that dietary cholesterol does not cross the blood–brain barrier and that SLOS cells have impaired intracellular cholesterol transport, the efficacy of cholesterol supplementation is likely limited (Wassif et al., 2002; Dietschy, 2009). Other targeted therapies have also been attempted, but none have been validated by controlled studies. Bile acid replacement has been used with cholestatic liver disease in infancy. Fresh frozen plasma, which contains high levels of cholesterol-rich lipoproteins such as LDL, has been used in acutely ill or severely stressed patients and in the setting of fetal intravenous and intraperitoneal transfusion. Stress steroid dosing has been used when there is evidence of adrenal insufficiency. A 3-hydroxy-3-methyl-glutarylCoA reductase inhibitor (simvastatin) has been used to improve cholesterol profiles, but its use had to be stopped in one individual who experienced liver dysfunction (Bianconi et al., 2015). Additionally, there may be a role for antioxidants in SLOS since 7DHC is highly reactive and gives rise to biologically active oxysterols (Korade et al., 2014). Direct delivery of cholesterol to the CNS by low-pressure catheter infusions has been proposed but not tested (Yu and Patel, 2005). Gene therapy, the use of neuroactive steroids, and inhibition of glycosphingolipids are also being investigated as possible therapeutic options in SLOS (Merkens et al., 2009). Even without proven targeted treatments, appropriate supportive management is important. Following the initial diagnosis, to establish the extent of disease and the needs of the individual, recommended evaluations include a developmental assessment, an ophthalmologic evaluation, ECG, echocardiogram, a musculoskeletal evaluation especially for the need for orthotics, a genital urinary examination, nutritional assessment, renal ultrasonography, brain magnetic resonance imaging, hearing evaluation, GI evaluation with special effort to evaluate the patient for pyloric stenosis, gastroesophageal reflux, and Hirschsprung disease if indicated, laboratory evaluation to evaluate the patient for adrenal insufficiency and cholestatic liver disease, and a medical genetics consultation. Referral to early intervention and physical, occupational, and speech therapies is needed in many cases. Surgical interventions, such as gastrectomy tube insertion, surgical repair of cataracts, ptosis, or strabismus, pyloromyotomy, surgical repair of syndactyly or polydactyly, tendon release surgery in cases with significant hypertonia, and tympanostomy may be required in individuals with SLOS. Anesthetic complications of malignant hyperthermia have been reported. Treatment with medications with high affinity for the 7DHC reductase substrate may worsen the biochemical abnormalities so when medications such as haloperidol, trazodone, or aripiprazole are being used, potential benefits need to be weighed against the theoretical risk of worsening the underlying disease. Some infants with severe feeding problems benefit from use of

hypoallergenic, elemental formulas. Patients also need to avoid extended periods of sun exposure and use appropriate sun protection measures given the issue with photosensitivity (Nowaczyk, 1993).

Suggested Readings Barth PG. Sphingolipids. In: Fernandes J, Saudubray J-M, van den Berghe G, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 2nd ed. Berlin: Springer-Verlag; 1995:375-382. Beutler E, Grabowski GA, et al. Gaucher disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001:3635-3668. Bianconi SE, Cross JL, Wassif CA, Porter FD. Pathogenesis, epidemiology, diagnosis and clinical aspects of Smith-Lemli-Opitz syndrome. Expert Opin Orphan Drugs. 2015;3(3):267-280. Braverman NE, Raymond GV, Rizzo WB, et al. Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117(3):313-321. Fletcher JM. Screening for lysosomal storage disorders: a clinical perspective. J Inherit Metab Dis. 2006;29:405-408. Grunewald S. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta. 2009;1792(9):827-834. Jaeken J. Congenital disorders of glycosylation. Ann N Y Acad Sci. 2010; 1214:190-198. Klouwer FCC, Berendse K, Ferdinandusse S, et al. Zellweger spectrum disorders: clinical overview and management approach. Orphan J Rare Dis. 2015;10:151-161. Meikle PJ, Grasby DJ, Dean CJ, et al. Newborn screening for lysosomal storage disorders. Mol Genet Metab. 2006;88:307-314. Nowaczyk MJM, et al. Smith-Lemli-Opitz syndrome. In: Pagon RA, Adam MP, Ardinger HH, eds. GeneReviews. Seattle (WA): 1993. Ross LF. Newborn screening for lysosomal storage diseases: an ethical and policy analysis. J Inherit Metab Dis. 2012;35:627-634. Salveson R. Expansion of the New York State newborn screening panel and Krabbe disease: a systematic program evaluation. Columbia University Academic Commons, 2011; https://doi.org/10.7916/ D8J96D9C. Sparks S, Quijano-Roy S, Harper A, et al. Congenital muscular dystrophy overview. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle (WA): 1993. Staretz-Chacham O, Lang TC, LaMarca ME, et al. Lysosomal storage disorders in the newborn. Pediatrics. 2009;123:1191-1207. Stone DL, Sidransky E. Hydrops fetalis: lysosomal storage disorders in extremis. Adv Pedatr. 1999;46:409-440. Wasserstein MP, Andriola M, Arnold G, et al. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet Med. 2016;18(12):1235-1423. Waterham HR, Ebberink MS. Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta. 2012;1822: 1430-1441. Waterham HR, Ferdinandusse S, Wanders RJA. Human disorders of peroxisome metabolism and biogenesis. Biochim Biophys Acta. 2016; 1863(5):922-933. Complete references used in this text can be found online at www .expertconsult.com

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References Aebi M, Helenius A, Schenk B, et al. Carbohydrate-deficient glycoprotein syndromes become congenital disorders of glycosylation: an updated nomenclature for CDG. First International Workshop on CDGS. Glycoconj J. 1999;16(11):669-671. Almeida AM, Murakami Y, Baker A, et al. Targeted therapy for inherited GPI deficiency. N Engl J Med. 2007;356(16):1641-1647. Ballabio A, Gieselmann V. Lysosomal disorders: from storage to cellular damage. Biochim Biophys Acta. 2009;1793:684-696. Bargal R, Avidan N, Ben-Asher E, et al. Identification of the gene causing mucolipidosis type IV. Nat Genet. 2000;26:118-123. Barth PG. Sphingolipids. In: Fernandes J, Saudubray J-M, van den Berghe G, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 2nd ed. Berlin: Springer-Verlag; 1995:375-382. Beutler E, Grabowski GA, et al. Gaucher disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001:3635-3668. Bianconi SE, Cross JL, Wassif CA, Porter FD. Pathogenesis, epidemiology, diagnosis and clinical aspects of Smith-Lemli-Opitz syndrome. Expert Opin Orphan Drugs. 2015;3(3):267-280. Boccuto L, Aoki K, Flanagan-Steet H, et al. A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation. Hum Mol Genet. 2014;23(2):418-433. Boukhris A, Schule R, Loureiro JL, et al. Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet. 2013;93(1):118-123. Braverman NE, D’Agostino MD, MacLean GE. Peroxisome biogenesis disorders: biological, clinical and pathophysiological perspectives. Dev Disbil Res Rev. 2013;17:187-196. Braverman NE, Raymond GV, Rizzo WB, et al. Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117(3):313-321. Buchholz T, Molitor G, Lukong KE, et al. Clinical presentation of congenital sialidosis in a patient with a neuraminidase gene frameshift mutation. Eur J Pediatr. 2001;160:26-30. Burton BK, Balwani M, Feillet F, et al. A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. N Engl J Med. 2015;373: 1010-1020. Carrozzo R, Bellini C, Lucioli S, et al. Peroxisomal acyl-CoA oxidase deficiency: two new cases. Am J Med Genet A. 2008;146A(13): 1676-1681. Chang S, Ren G, Steiner RD, et al. Elevated autophagy and mitochondrial dysfunction in the Smith-Lemli-Opitz syndrome. Mol Genet Metab Rep. 2014;1:431-442. Chao YH, Robak LA, Xia F, et al. Missense variants in the middle domain of DNM1L in cases of infantile encephalopathy alter peroxisomes and mitochondria when assayed in Drosophila. Hum Mol Genet. 2016; 25(9):1846-1856. Chitayat D, Meunier CM, Hodgkinson KA, et al. Mucolipidosis type IV: clinical manifestations and natural history. Am J Med Genet. 1991;41:313-318. Cooper MK, Wassif CA, Krakowiak PA, et al. A defective response to hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet. 2003;33(4):508-513. Corzo D, Gibson W, Johnson K, et al. Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet. 2002;70:1520-1531. Cross JL, Iben J, Simpson CL, et al. Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets. Clin Genet. 2015;87(6):570-575. de Lonlay P, Seta N. The clinical spectrum of phosphomannose isomerase deficiency, with an evaluation of mannose treatment for CDG-Ib. Biochim Biophys Acta. 2009;1792(9):841-843.

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Dietschy JM. Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol Chem. 2009;390(4):287-293. Duffner PK, Caggana M, Orsini JJ, et al. Newborn screening for Krabbe disease: the New York State model. Pediatr Neurol. 2009;40: 245-252. El Hajj HI, Vluggens A, Andreoletti P, et al. The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy). Endocrinology. 2012;153(6):2568-2575. Ellingson MS, Wick MJ, White WM, et al. Pregnancy in an individual with mild Smith-Lemli-Opitz syndrome. Clin Genet. 2014;85(5): 495-497. Endo T. Glycobiology of alpha-dystroglycan and muscular dystrophy. J Biochem. 2015;157(1):1-12. Erikson A, Johansson K, Mansson JE, Svennerholm L. Enzyme replacement therapy of infantile Gaucher disease. Neuropediatrics. 1993;24: 237-238. Escolar ML, Poe MD, Martin HR, et al. A staging system for infantile Krabbe disease to predict outcome after unrelated umbilical cord blood transplantation. Pediatrics. 2006;118:879-889. Escolar ML, Poe MD, Provenzale JM, et al. Transplantation of umbilicalcord blood in babies with infantile Krabbe’s disease. N Engl J Med. 2005;352:2069-2081. Farese RV Jr, Herz J. Cholesterol metabolism and embryogenesis. Trends Genet. 1998;14(3):115-120. Ferdinandusse S, van Grunsven EG, Oostheim W, et al. Reinvestigation of peroxisomal 3-ketoacyl-CoA thiolase deficiency: identification of the true defect at the level of D-bifunctional protein. Am J Hum Genet. 2002;70:1589-1593. Ferguson MAJ, Kinoshita T, Hart GW. Glycosylphosphatidylinositol anchors. In: Varki A, Cummings RD, Esko JD, et al., eds. Essentials of Glycobiology. 2nd ed. NY: Cold Spring Harbor; 2009. Fletcher JM. Screening for lysosomal storage disorders: a clinical perspective. J Inherit Metab Dis. 2006;29:405-408. Freeze HH, Chong JX, Bamshad MJ, Ng BG. Solving glycosylation disorders: fundamental approaches reveal complicated pathways. Am J Hum Genet. 2014;94(2):161-175. Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurology of inherited glycosylation disorders. Lancet Neurol. 2012;11(5):453-466. Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurological aspects of human glycosylation disorders. Annu Rev Neurosci. 2015;38: 105-125. Freeze HH, Schachter H. Genetic disorders of glycosylation. In: Varki A, Cummings RD, Esko JD, et al., eds. Essentials of Glycobiology. 2nd ed. NY: Cold Spring Harbor; 2009. Fujimoto A, Tayebi N, Sidransky E. Congenital ichthyosis preceding neurologic symptoms in two sibs with type 2 Gaucher disease. Am J Med Genet. 1995;59:356-358. Funke S, Gardeitchik T, Kouwenberg D, et al. Perinatal and early infantile symptoms in congenital disorders of glycosylation. Am J Med Genet A. 2013;161A(3):578-584. Goldfischer S, Collins J, Rapin I, et al. Pseudo-Zellweger syndrome: deficiencies in several peroxisomal oxidative activities. J Pediatr. 1986;108:25-35. Gould S, Raymond G, Valle D. The peroxisome biogenesis disorders. In: Valle D, Beaudet AL, Vogelstein B, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001:3181-3217. Grunewald S. Congenital disorders of glycosylation: rapidly enlarging group of (neuro)metabolic disorders. Early Hum Dev. 2007;83(12): 825-830. Grunewald S. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta. 2009;1792(9):827-834. He M, Matern D, Raymond KM, Wolfe L. The congenital disorders of glycosylation. In: Garg U, Smith LD, Heese BA, eds. Laboratory Diagnosis: Inherited Metabolic Diseases. Washington, DC: AACC Press; 2012;252:177-195. Hennet T. Diseases of glycosylation beyond classical congenital disorders of glycosylation. Biochim Biophys Acta. 2012;1820(9):1306-1317.

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PART V I  Metabolic Disorders of the Newborn

Honda A, Tint GS, Salen G, et al. Defective conversion of 7-dehydrocholesterol to cholesterol in cultured skin fibroblasts from Smith-LemliOpitz syndrome homozygotes. J Lipid Res. 1995;36(7):1595-1601. Hopkins PV, Campbell C, Klug T, et al. Lysosomal storage disorder screening implementation: findings from the first six months of full population pilot testing in Missouri. J Pediatr. 2015;166:172-177. Hoogerbrugge PM, Brouwer OF, Bordigoni P, et al. Allogenic bone marrow transplantation for lysosomal storage diseases. Lancet. 1995;345: 1398-1402. Ince Z, Coban A, Peker O, Ince U, Can G. Gaucher disease associated with congenital ichthyosis in the neonate. Eur J Pediatr. 1995;154:418. Irons M, Elias ER, Abuelo D, et al. Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial. Am J Med Genet. 1997;68(3): 311-314. Irons M, Elias ER, Salen G, et al. Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet. 1993;341(8857):1414. Iwasa M, Yamagata T, Mizuguchi M, et al. Contiguous ABCD1 DXS1357E deletion syndrome: report of an autopsy case. Neuropathology. 2013; 33(3):292-298. Jaeken J. Congenital disorders of glycosylation. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 4th, rev. ed. Heidelberg: Springer; 2006:523-530. Jaeken J. Congenital disorders of glycosylation. Ann N Y Acad Sci. 2010;1214:190-198. Jaeken J. Congenital disorders of glycosylation (CDG): it’s (nearly) all in it! J Inherit Metab Dis. 2011;34(4):853-858. Jaeken J. Congenital disorders of glycosylation. In: Saudubray JM, Van den Berghe G, Walter J, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 5th ed. Berlin: Springer; 2012;656:608-616. Jaeken J, Hennet T, Matthijs G, Freeze HH. CDG nomenclature: time for a change! Biochim Biophys Acta. 2009;1792(9):825-826. Jaeken J, Matthijs G. Congenital disorders of glycosylation: a rapidly expanding disease family. Annu Rev Genomics Hum Genet. 2007;8: 261-278. Jaeken J, van Eijk HG, van der Heul C, et al. Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome. Clin Chim Acta. 1984;144(2–3):245-247. Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P, et al. Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG-deficiency, increased serum arylsulfatase-A and increased CSF protein - new syndrome. Pediatr Res. 1980;14(2):179. Jezela-Stanek A, Ciara E, Malunowicz EM, et al. Mild Smith-Lemli-Opitz syndrome: further delineation of 5 Polish cases and review of the literature. Eur J Med Genet. 2008;51(2):124-140. Jezela-Stanek A, Ciara E, Piekutowska-Abramczuk D, et al. Congenital disorder of glycosylphosphatidylinositol (GPI)-anchor biosynthesis—the phenotype of two patients with novel mutations in the PIGN and PGAP2 genes. Eur J Paediatr Neurol. 2016;20(3):462-473. Kelley RI, Hennekam RC. The Smith-Lemli-Opitz syndrome. J Med Genet. 2000;37(5):321-335. Kinoshita T, Fujita M, Maeda Y. Biosynthesis, remodelling and functions of mammalian GPI-anchored proteins: recent progress. J Biochem. 2008;144(3):287-294. Kiselyov K, Jennings JJ, Rbaibi Y. Autophagy, mitochondria and cell death in lysosomal storage diseases. Autophagy. 2007;3:259-262. Klouwer FCC, Berendse K, Ferdinandusse S, et al. Zellweger spectrum disorders: clinical overview and management approach. Orphan J Rare Dis. 2015;10:151-161. Kohlschütter A, Sieg K, Schulte FJ, Hayek HW, Goebel HH. Infantile cardiomyopathy and neuromyopathy with beta-galactosidase deficiency. Eur J Pediatr. 1982;139:75-81. Korade Z, Xu L, Harrison FE, et al. Antioxidant supplementation ameliorates molecular deficits in Smith-Lemli-Opitz syndrome. Biol Psychiatry. 2014;75(3):215-222. Krasnewich D, O’Brien K, Sparks S. Clinical features in adults with congenital disorders of glycosylation type Ia (CDG-Ia). Am J Med Genet C Semin Med Genet. 2007;145C(3):302-306. Krivit W, Peters C, Dusenbery K, et al. Wolman disease successfully treated by bone marrow transplantation. Bone Marrow Transplant. 2000;23: 567-570.

Lanthaler B, Steichen-Gersdorf E, Kollerits B, Zschocke J, WitschBaumgartner M. Maternal ABCA1 genotype is associated with severity of Smith-Lemli-Opitz syndrome and with viability of patients homozygous for null mutations. Eur J Hum Genet. 2013;21(3): 286-293. Lee RW, McGready J, Conley SK, et al. Growth charts for individuals with Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2012;158A(11): 2707-2713. Lee PR, Raymond GV. Child neurology: Zellweger syndrome. Neurology. 2013;80:e207-e210. Lemyre E, Russo P, Melancon SB, et al. Clinical spectrum of infantile free sialic acid storage disease. Am J Med Genet. 1999;82:385-391. Lesnik Oberstein SA, Kriek M, White SJ, et al. Peters plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase. Am J Hum Genet. 2006;79(3):562-566. Li Y, Brockmann K, Turecek F, et al. Tandem mass spectrometry for the direct assay of enzymes in dried blood spots: application to newborn screening for Krabbe disease. Clin Chem. 2004a;50:638-640. Li Y, Scott CR, Chamoles NA, et al. Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening. Clin Chem. 2004b;50:1785-1796. Lin DS, Steiner RD, Flavell DP, Connor WE. Intestinal absorption of cholesterol by patients with Smith-Lemli-Opitz syndrome. Pediatr Res. 2005;57(6):765-770. Lipson AH, Rogers M, Berry A. Collodion babies with Gaucher’s disease: a further case. Arch Dis Child. 1991;66:667. Liu K, Commens C, Choong R, Jaworski R. Collodion babies with Gaucher’s disease. Arch Dis Child. 1988;63:854-856. Marquardt T, Luhn K, Srikrishna G, et al. Correction of leukocyte adhesion deficiency type II with oral fucose. Blood. 1999;94(12):3976-3985. McCabe ERB, Fine BA, Golbus MS, et al. Gaucher disease: current issues in diagnosis and treatment. JAMA. 1996;275:548-553. Meikle PJ, Grasby DJ, Dean CJ, et al. Newborn screening for lysosomal storage disorders. Mol Genet Metab. 2006;88:307-314. Mercuri E, Messina S, Bruno C, et al. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology. 2009;72(21):1802-1809. Merkens LS, Wassif C, Healy K, et al. Smith-Lemli-Opitz syndrome and inborn errors of cholesterol synthesis: summary of the 2007 SLO/ RSH Foundation scientific conference sponsored by the National Institutes of Health. Genet Med. 2009;11(5):359-364. Millat G, Chikh K, Naureckiene S, et al. Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am J Hum Genet. 2001;69:1013-1021. Morava E. Galactose supplementation in phosphoglucomutase-1 deficiency; review and outlook for a novel treatable CDG. Mol Genet Metab. 2014;112(4):275-279. Natowicz MR, Stoler JM, Prence EM, Liscum L. Marked heterogeneity in Niemann-Pick disease, type C: clinical and ultrastructural findings. Clin Pediatr. 1995;34:190-197. Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012; 49(6):353-361. Nowaczyk MJM. Smith-Lemli-Opitz syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle (WA): 1993. Parker AM, Sunness JS, Beneton NH, et al. Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial. Neurology. 2010;75(9):826-830. Paulick MG, Bertozzi CR. The glycosylphosphatidylinositol anchor: a complex membrane-anchoring structure for proteins. Biochemistry. 2008;47(27):6991-7000. Poll-The BT, Gärtner J. Clinical diagnosis, biochemical findings and MRI spectrum of peroxisomal disorders. Biochim Biophys Acta. 2012;1822: 1421-1429. Poll-The BT, Roels F, Ogier H, et al. A new peroxisomal disorder with enlarged peroxisomes and a specific deficiency of acyl-CoA oxidase (pseudo-neonatal adrenoleukodystrophy). Am J Hum Genet. 1988;42:422-434. Porter FD. Smith-Lemli-Opitz syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2008;16(5):535-541.

CHAPTER 23  Lysosomal Storage, Peroxisomal, and Glycosylation Disorders and SLOS Presenting in the Neonate

Rader DJ. Lysosomal acid lipase deficiency - a new therapy for a genetic lipid disease. N Engl J Med. 2015;373:1071-1073. Ratbi I, Falkenberg KD, Sommen M, et al. Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6. Am J Hum Genet. 2015;97:535-545. Ross LF. Newborn screening for lysosomal storage diseases: an ethical and policy analysis. J Inherit Metab Dis. 2012;35:627-634. Salveson R. Expansion of the New York State newborn screening panel and Krabbe disease: a systematic program evaluation. Columbia University Academic Commons, 2011; https://doi.org/10.7916/ D8J96D9C. Schrader M, Bonekamp NA, Islinger M. Fission and proliferation of peroxisomes. Biochimica et Biophysica Acta. 2012:1822;1343-1357. Setchell KDR, Heubi JE, Bove KE, et al. Liver disease caused by a failure to racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid therapy. Gastroenterology. 2003;124:217-232. Sheffer R, Douiev L, Edvardson S, et al. Postnatal microcephaly and pain insensitivity due to a de novo heterozygous DNM1L mutation causing impaired mitochondrial fission and function. Am J Med Genet. 2016;170(6):1603-1607. Sherer DM, Metlay LA, Sinkin RA, et al. Congenital ichthyosis with restrictive dermopathy and Gaucher disease: a new syndrome with associated prenatal diagnostic and pathology findings. Obstet Gynecol. 1993;81:842-844. Shimozawa N. Molecular and clinical findings and diagnostic flowchart of peroxisomal diseases. Brain Dev. 2011;33:770-776. Sidransky E, Sherer DM, Ginns EI. Gaucher disease in the neonate: a distinct Gaucher phenotype is analogous to a mouse model created by targeted disruption of the glucocerebrosidase gene. Pediatr Res. 1992;32:494-498. Smith DW, Lemli L, Opitz JM. A newly recognized syndrome of multiple congenital anomalies. J Pediatr. 1964;64:210-217. Sokal EM, Smets F, Bourgois A, et al. Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis disease: technique, safety, and metabolic follow-up. Transplantation. 2003;76(4): 735-738. Sparks S, Quijano-Roy S, Harper A, et al. Congenital muscular dystrophy overview. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle (WA): 1993. Sparks SE, Krasnewich DM. Congenital disorders of N-linked glycosylation pathway overview. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle (WA): 1993. Staretz-Chacham O, Lang TC, LaMarca ME, Krasnewich D, Sidransky E. Lysosomal storage disorders in the newborn. Pediatrics. 2009;123: 1191-1207. Stewart WA, Gordon KE, Camfield PR, Wood EP, Dooley JM. Irritability in Krabbe’s disease: dramatic response to low-dose morphine. Pediatr Neurol. 2001;25:344-345. Stone DL, Sidransky E. Hydrops fetalis: lysosomal storage disorders in extremis. Adv Pedatr. 1999;46:409-440. Sturiale L, Barone R, Garozzo D. The impact of mass spectrometry in the diagnosis of congenital disorders of glycosylation. J Inherit Metab Dis. 2011;34(4):891-899. Sun M, Goldin E, Stahl S, et al. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet. 2000;9:2471-2478. Thiel C, Korner C. Therapies and therapeutic approaches in congenital disorders of glycosylation. Glycoconj J. 2013;30(1):77-84. Tierney E, Conley SK, Goodwin H, Porter FD. Analysis of short-term behavioral effects of dietary cholesterol supplementation in SmithLemli-Opitz syndrome. Am J Med Genet A. 2010;152A(1):91-95. Timal S, Hoischen A, Lehle L, et al. Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing. Hum Mol Genet. 2012;21(19):4151-4161. Tint GS, Irons M, Elias ER, et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med. 1994;330(2):107-113. Tint GS, Salen G, Batta AK, et al. Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. J Pediatr. 1995;127(1):82-87.

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Topaloglu H. Abnormal glycosylation of the alpha-dystroglycan: deficient sugars are no good. Neurology. 2009;72(21):1798-1799. Ungar D, Oka T, Brittle EE, et al. Characterization of a mammalian Golgi-localized protein complex, COG, that is required for normal Golgi morphology and function. J Cell Biol. 2002;157(3): 405-415. Van Maldergem L, Moser AB, Vincent MF, et al. Orthotopic liver transplantation from a living-related donor in an infant with a peroxisome biogenesis defect of the infantile Refsum disease type. J Inherit Metab Dis. 2005;28(4):593-600. Vanstone JR, Smith AM, McBride S, et al. DNM1L-related mitochondrial fission defect presenting as refractory epilepsy. Eur J Hum Genet. 2016;24(7):1084-1088. Vogler C, Levy B, Galvin NJ, et al. Enzyme replacement in murine mucopolysaccharidosis type VII: neuronal and glial response to β-glucuronidase requires early initiation of enzyme replacement therapy. Pediatr Res. 1999;45:838-844. Wang RY, Monuki ES, Powers J, et al. Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study. J Inherit Metab Dis. 2015;37(5):791-799. Wasserstein MP, Andriola M, Arnold G, et al. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet Med. 2016;18(12):1235-1423. Wassif CA, Maslen C, Kachilele-Linjewile S, et al. Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet. 1998;63(1):55-62. Wassif CA, Vied D, Tsokos M, et al. Cholesterol storage defect in RSH/ Smith-Lemli-Opitz syndrome fibroblasts. Mol Genet Metab. 2002;75(4):325-334. Waterham HR, Clayton P. Disorders of cholesterol synthesis. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 4th, rev. ed. Heidelberg: Springer; 2006: 414-415. Waterham HR, Ebberink MS. Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta. 2012;1822: 1430-1441. Waterham HR, Ferdinandusse S, Wanders RJA. Human disorders of peroxisome metabolism and biogenesis. Biochim Biophys Acta. 2016;1863(5):922-933. Waterham HR, Hennekam RC. Mutational spectrum of Smith-Lemli-Opitz syndrome. Am J Med Genet C Semin Med Genet. 2012;160C(4): 263-284. Waterham HR, Koster J, van Roermund CWT, et al. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007;356: 1736-1741. Weiss K, Gonzalez AN, Lopez G, et al. The clinical management of type 2 Gaucher disease. Mol Genet Metab. 2015;114:110-122. Wenger DA, Coppola S, Liu SL. Insights into the diagnosis and treatment of lysosomal storage diseases. Arch Neurol. 2003;60: 322-328. Whitley CG, Spielmann RC, Herro G, Teragawa SS. Urinary glycosaminoglycan excretion quantified by an automated semimicro method in specimens conveniently transported from around the globe. Mol Genet Metab. 2002;75:56-64. Winchester B, Vellodi A, Young E. The molecular basis of lysosomal storage diseases and their treatment. Biochem Soc Trans. 2000;28: 150-154. Witsch-Baumgartner M, Gruber M, Kraft HG, et al. Maternal apo E genotype is a modifier of the Smith-Lemli-Opitz syndrome. J Med Genet. 2004;41(8):577-584. Wolman M. Wolman disease and its treatment. Clin Pediatr. 1995;34: 207-212. Wraith JE, Baumgartner MR, Bembi B, et al. Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab. 2009;98:152-165. Xu L, Porter NA. Free radical oxidation of cholesterol and its precursors: implications in cholesterol biosynthesis disorders. Free Radic Res. 2015;49(7):835-849. Yu H, Patel SB. Recent insights into the Smith-Lemli-Opitz syndrome. Clin Genet. 2005;68(5):383-391.

PA RT V II   Basic Newborn Care

24 

Newborn Resuscitation ANUP KATHERIA AND NEIL N. FINER

KEY POINTS • Adequate preparation for newborn resuscitation ensures that care can be provided in a timely and competent manner. • Avoiding early umbilical cord clamping following delivery may have a significant impact on newborn outcomes. • The use of additional monitoring (such as electrocardiography, carbon dioxide detection, and respiratory function) can be helpful during resuscitation.

T

he transition from fetal to neonatal life is a dramatic and complex process involving extensive physiologic changes that are most obvious at the time of birth. Individuals who care for newborns must monitor the progress of this transition and be prepared to intervene when necessary. In most births this transition occurs without a requirement for any significant assistance. However, when the need for intervention arises, the presence of providers skilled in neonatal resuscitation can be lifesaving. Each year approximately 4 million children are born in the United States (Martin et al., 2008), and more than 30 times as many are born worldwide. It is estimated that approximately 5%–10% of all births will require some form of resuscitation beyond basic care, making neonatal resuscitation the most frequently practiced form of resuscitation in medical care. Throughout the world approximately 1 million newborn deaths are associated with birth asphyxia (Lawn et al., 2005). While early effective newborn resuscitation will not eliminate all early neonatal deaths, such intervention will save many lives and significantly reduce subsequent morbidities. Attempts to revive nonbreathing newborns immediately after birth have been made throughout recorded time, with references in the literature, religion, and early medicine. Although the organization and sophistication have changed, the basic principle and goal of initiating breathing has remained constant throughout time. It has been just in the last 30 years that more attention has been focused on the process of neonatal resuscitation. Resuscitation programs in other areas of medicine were initiated in the 1970s in an effort to improve knowledge of effective resuscitation and provide an action plan for early responders. The first such program (1974) was focused on adult cardiopulmonary resuscitation. These programs then began increasing in complexity and becoming

more specific to different types of resuscitation needs. With the collaboration of the American Heart Association and the American Academy of Pediatrics, the Neonatal Resuscitation Program (NRP) was initiated in 1987—designed to address the specific needs of the newborn. Recent editions of the NRP textbook (Kattwinkel 2006) contained several revisions, including specific recommendations for the preterm newborn. Various groups throughout the world also provide resuscitation recommendations that may be more specific to the practices in certain regions. An international group of scientists, the International Liaison Committee on Resuscitation (ILCOR), meets on a regular basis to review available resuscitation evidence for all the different areas of resuscitation and puts forth a summary of its review (Chamberlain, 2005). The most recent recommendation by ILCOR (Perlman et al., 2015) and the recommendations in the seventh edition of the NRP textbook (2016) are outlined in this review. The overall goal of the NRP is similar to that of other resuscitation programs in that it intends to teach large groups of individuals of varied backgrounds the principles of newborn resuscitation and to provide an action plan for providers. Similarly, a satisfactory end result of resuscitation would be common to all forms of resuscitation: namely, to provide adequate tissue oxygenation to prevent tissue injury and restore spontaneous cardiopulmonary function. However, when one is comparing neonatal resuscitation with other forms of resuscitation, there are two distinctions. First, the birth of a child is a more predictable occurrence than most events requiring resuscitation in an adult such as an arrhythmia or a myocardial infarction. While not every birth will require “resuscitation,” it is more reasonable to expect that skilled individuals can be present when the need for neonatal resuscitation arises. It is possible to anticipate with some accuracy which newborns will more likely require resuscitation on the basis of perinatal factors and thus allow time for preparation. The second distinction of neonatal resuscitation compared with other forms of resuscitation involves the unique physiology involved in the normal transition from fetal to neonatal life. The fetus exists in the protected environment of the uterus, where temperature is closely controlled, the lungs are filled with fluid, continuous fetal breathing is not essential, and the gas exchange organ is the placenta. The transition that occurs at birth requires the newborn to increase heat production, initiate continuous breathing, replace the lung fluid with air/oxygen, and significantly increase pulmonary blood 273

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flow so that gas exchange can occur in the lungs. The expectations for this transitional process and knowledge of how to effectively assist the process help guide the current practice of newborn resuscitation.

Transition From Fetal to Extrauterine Life While the complete transition from fetal to extrauterine life is complex and much more intricate than can be discussed in a few short paragraphs, basic knowledge of these processes will contribute to the understanding of the rationale for resuscitation practices. The key elements necessary for a successful transition to extrauterine life involve changes in thermoregulation, respiration, and circulation. In utero, the fetal core temperature is approximately 0.5°C greater than the mother’s temperature (Gunn and Gluckman, 1983). Heat is produced by metabolic processes and is lost over this small temperature gradient through the placenta and skin (Gilbert et al., 1985). After birth the temperature gradient between the newborn and the environment becomes much greater, and heat is lost through the skin by radiation, convection, conduction, and evaporation. The newborn must begin producing heat through other mechanisms, such as lipolysis of brown adipose tissue (Dawkins and Scopes, 1965). If heat is lost at a pace greater than it is produced, the newborn will become hypothermic. Preterm newborns are at particular risk because of increased heat loss through immature skin, a greater surface area to body weight ratio, and decreased brown adipose tissue stores. The fetus lives in a fluid-filled environment, and the developing alveolar spaces are filled with lung fluid. Lung fluid production decreases in the days before delivery (Kitterman et al., 1979), and the remainder of lung fluid is reabsorbed into the pulmonary interstitial spaces after delivery (Bland, 1988). As the newborn takes its first breaths after birth, a negative intrathoracic pressure of approximately 50 cmH2O is generated (Vyas et al., 1986). The alveoli become filled with air, and with the help of pulmonary surfactant, the lungs retain a small amount of air persisting at the end of exhalation that is known as the functional residual capacity (FRC). Although the fetus makes breathing movements in utero, these efforts are intermittent and are not required for fetal gas exchange. Continuous spontaneous breathing is maintained after birth by several mechanisms, including the activation of chemoreceptors, the decrease in the levels of hormones that inhibit respirations, and the presence of natural environmental stimulation. Spontaneous breathing can be suppressed at birth for several reasons, most critical of which is the presence of acidosis secondary to compromised fetal circulation. The natural history of the physiologic responses to asphyxia and acidosis has been described by researchers evaluating animal models. Dawes (1968) described the breathing response to acidosis in different animal species. He noted that when the pH is decreased, animals typically have a relatively short period of apnea followed by gasping. The gasping pattern then increases in rate until breathing ceases again for a second period of apnea. The physiologic effects that occur with worsening acidosis are noted in Fig. 24.1. Dawes also noted that the first period, or primary apnea, could be reversed with stimulation, while the second period, secondary or terminal apnea, required assisted ventilation to ultimately establish spontaneous breathing. The first sign of improvement was noted to be an increase in heart rate. Further recovery was noted when the newborn begins gasping again. The secondary period of apnea differs in duration depending on the duration of asphyxia and the degree of acidosis. In the clinical situation the exact timing of the onset of acidosis is generally

Respiratory Effort

Heart Rate

Aortic Blood Pressure Central Venous Pressure

Cardiac Output

Blood Flow, Head & Heart

Blood Flow, Body

Blood Flow, Lungs

Brain Damage Time pH

7.4

7.1

7.0

6.7

Asphyxia Resuscitation

• Fig. 24.1  The Sequence of Cardiopulmonary Changes With Asphyxia

and Resuscitation. Time is on the horizontal axis. Asphyxia progresses from left to right; resuscitation proceeds from right to left. Units of time are not given. If there is complete interruption of respiratory gas exchange, the entire process of asphyxia from extreme left to right could occur in approximately 10 minutes. It could take much longer with an asphyxiating process that only partly interrupts gas exchange or does so completely but only for repeated brief periods. With resuscitation, the process reverses, beginning at the point to which asphyxia has proceeded. The blue dotted line is the reversal of asphyxia with resuscitation. (Modified from Dawes G. Foetal and Neonatal Physiology. Chicago: Year Book; 1968; and Avery GN. Neonatology. Philadelphia: JB Lippincott; 1987.)

unknown, and therefore any observed apnea may be either primary or secondary. This is the basis of the resuscitation recommendation that stimulation may be attempted in the presence of apnea, but if it is not quickly successful, assisted ventilation should be initiated promptly. Without the presence of acidosis a newborn may also develop apnea because of recent exposure to respiratory-suppressing medications such as narcotics, anesthetics, and magnesium. These medications when given to the mother cross the placenta and depending on the time of administration and dose may depress the newborn’s respiratory drive. Fetal circulation is unique because gas exchange occurs in the placenta. In the fetal heart, oxygenated blood returning via the umbilical vein is mixed with deoxygenated blood from the superior vena cava and inferior vena cava and is differentially distributed throughout the body. The most oxygenated blood is directed toward the brain, while the most deoxygenated blood is directed toward the placenta. Thus blood returning from the placenta to the right atrium is preferentially streamed via the foramen ovale to the left atrium and left ventricle and then to the ascending aorta, providing the brain with the most oxygenated blood. Fetal channels, including the ductus arteriosus and foramen ovale, allow most blood flow to bypass the lungs with their intrinsically high vascular resistance,

CHAPTER 24  Newborn Resuscitation

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• Fig. 24.3 Circulation • Fig. 24.2  Fetal

Circulation. Oxygenated blood leaves the placenta by way of the umbilical vein (vessel without stippling). The blood flows into the portal sinus in the liver (not shown), and a variable portion of it perfuses the liver. The remainder passes from the portal sinus through the ductus venosus into the inferior vena cava, where it joins blood from the viscera (represented by the kidney, gut, and skin). Approximately half of the inferior vena cava flow passes through the foramen ovale to the left atrium, where it mixes with a small amount of pulmonary venous blood. This relatively well oxygenated blood (light stippling) supplies the heart and brain by way of the ascending aorta. The other half of the inferior vena cava stream mixes with superior vena cava blood and enters the right ventricle (blood in the right atrium and ventricle has little oxygen, which is denoted by heavy stippling). Because the pulmonary arterioles are constricted, most of the blood in the main pulmonary artery flows through the ductus arteriosus (DA), so the descending aorta’s blood has less oxygen (heavy stippling) than blood in the ascending aorta (light stippling). (From Avery GN. Neonatology. Philadelphia: JB Lippincott; 1987.)

and as a result pulmonary blood flow is approximately 8% of the total cardiac output. In the mature postnatal circulation the lungs must receive 100% of the cardiac output. When the low-resistance placental circulation is removed after birth, the newborn’s systemic vascular resistance increases, while the pulmonary vascular resistance begins to fall as a result of pulmonary expansion, increased arterial and alveolar oxygen tension, and local vasodilators. These changes result in a dramatic increase in pulmonary blood flow. The average fetal oxyhemoglobin saturation as measured in fetal lambs is approximately 50% (Nijland et al., 1995) but ranges in different sites within the fetal circulation between 20%–80% (Teitel, 1988). The oxyhemoglobin saturation rises gradually over the first 5–15 minutes of life to 90% or greater as the air spaces are cleared of fluid. Diagrams of the blood flow patterns in the fetus and normally transitioning newborn are shown in Figs. 24.2–24.3. In the face of poor transition secondary to asphyxia, meconium aspiration,

in the Normal Newborn. After expansion of the lungs and ligation of the umbilical cord, pulmonary blood flow increases and left atrial and systemic arterial pressures increase, while pulmonary arterial and right-sided heart pressures decrease. When the left atrial pressure exceeds the right atrial pressure, the foramen ovale closes so that all of the inferior and superior vena cava blood leave the right atrium, enter the right ventricle, and are pumped through the pulmonary artery toward the lung. With the increase in systemic arterial pressure and decrease in pulmonary arterial pressure, flow through the ductus arteriosus becomes left-to-right, and the ductus arteriosus constricts and closes. The course of the circulation is the same as in the adult. (From Avery GN. Neonatology. Philadelphia: JB Lippincott; 1987.)

pneumonia, or extreme prematurity, the lungs may not be able to develop efficient gas exchange, and thus the oxygen saturation may not increase as expected. In addition, in some situations the normal reduction in pulmonary vascular resistance may not fully occur, resulting in persistent pulmonary hypertension and decreased effective pulmonary blood flow with continued right to left shunting through the aforementioned fetal channels. This will lead to persistent hypoxemia and potentially to significant newborn illness requiring intensive care until the circulatory pattern adjusts to extrauterine life. The circulatory pattern associated with poor transition is noted in Fig. 24.4.

Environment and Preparation The environment in which the newborn is born should facilitate the transition to neonatal life as much as possible and should be able to readily accommodate the needs of a resuscitation team when necessary. Hospitals differ in their approach to the details of how to prepare for resuscitation. For example, some hospitals have a separate room designated for resuscitation where the newborn will be taken after birth, while others have the delivery room adjacent to the neonatal intensive care unit (NICU), and the newborn is resuscitated in the NICU if necessary. Hospitals may

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TABLE 24.1 

Risk Factors for Neonatal Resuscitation

Maternal Factors

Fetal Factors

Intrapartum Factors

Maternal hypertension

Preterm delivery

Opiates in labor

Maternal infection

Breech presentation

Rupture of membranes >18 h

Multiple gestations (preterm)

Shoulder dystocia

Meconium-stained amniotic fluid Nonreassuring fetal heart rate patterns Emergency cesarean delivery Prolapsed cord

Data from Aziz K, Chadwick M, Baker M, Andrews E. Ante- and intra-partum factors that predict increased need for neonatal resuscitation. Resuscitation. 2008;79(3):444–452.

• Fig. 24.4 Circulation

in an Asphyxiated Newborn With Incomplete Expansion of the Lungs. Pulmonary vascular resistance is high, pulmonary blood flow is low (normal number of pulmonary veins), and flow through the ductus arteriosus is high. With little pulmonary arterial flow, left atrial pressure decreases below right atrial pressure, the foramen ovale opens, and vena cava blood flows through the foramen into the left atrium. Partially venous blood goes to the brain via the ascending aorta. The blood of the descending aorta that goes to the viscera has less oxygen than that of the ascending aorta (heavy stippling) because of the reverse flow through the ductus arteriosus. Therefore the circulation is the same as in the fetus, except that there is less well-oxygenated blood in the inferior vena cava and umbilical vein. (From Avery GN. Neonatology. Philadelphia: JB Lippincott; 1987.)

bring all the necessary equipment into the delivery room when resuscitation is expected or may have every delivery room already equipped for any resuscitation. Wherever the resuscitation will happen, a few key elements must be considered. The room should be warm enough to prevent excessive newborn heat loss, bright enough for assessment of the newborn’s clinical status, and large enough to accommodate the necessary personnel and equipment to care for the baby. When no added risks to the newborn are identified, term births frequently occur without the attendance of a specific neonatal resuscitation team. However, it is recommended that one individual be present who is responsible only for the newborn and can quickly alert a neonatal resuscitation team if necessary. Even the best neonatal resuscitation triage systems will not anticipate the need for resuscitation in all cases. A review found that when a risk-based determination of neonatal resuscitation team attendance at deliveries was used, 22% of newborns at attended deliveries required at least assisted ventilation (Aziz et al., 2008). These investigators found that the most significant risk factors were preterm birth, emergency cesarean delivery, and meconium-stained amniotic fluid. Other significant risk factors for the need for resuscitation are listed in

Table 24.1. Antenatal determination of risk allows the resuscitation team to be present for the delivery and to be more thoroughly prepared for the situation. The composition of the neonatal resuscitation team will differ tremendously among institutions. Probably the most important factor in how well a team functions is how the team has prepared for the delivery. Preparation involves both the immediate tasks of readying equipment and personnel for an individual situation and the more broad institutional preparation of training team members and providing appropriate space and equipment. We believe that when there is a strong suspicion that the newborn will be born in a compromised state, a minimum of three team members should be present, including one member with significant experience in leading neonatal resuscitations. Each team member has assigned tasks that are performed on a regular basis. The leader is expected to ensure that the appropriate interventions are performed and that they are performed well. All team members are encouraged and expected to speak up if a problem is noticed or if they believe an alternative course would be beneficial. It seems logical that teams that regularly work together and divide tasks in a routine manner will have a better chance of functioning smoothly during a critical situation. Institutions can facilitate team readiness with regular review of practices and mock codes or simulator training to practice uncommon scenarios. In our institution, Sharp Mary Birch Hospital for Women & Newborns, we review recorded resuscitations monthly with representatives from all disciplines involved in the resuscitation team. This is done as a quality assurance procedure and allows ongoing identification of areas needing improvement (Carbine et al., 2000). Additionally, this practice provides an opportunity for education and discussion about potential solutions to repetitive problems of newborn resuscitation. We have also instituted a supplemental training program for our pediatric trainees to obtain experience in a preclinical situation (Garey, 2009). These training sessions allow adequate time to review scenarios in detail, and trainees are given the opportunity to prepare and operate the equipment and practice procedures on an individualized basis. Others have used simulators to provide additional resuscitation training (Halamek, 2008). All of these training elements help prepare teams for future resuscitations.

CHAPTER 24  Newborn Resuscitation

The process of neonatal resuscitation requires that the medical team make rapid medical decisions to effectively transition a newborn from fetal to neonatal life. If the possible need for resuscitation is anticipated, the use of checklists can help the care team prepare for the specific circumstances of the particular delivery, familiarize themselves with other team members and the team leader, reinforce appropriate communication, ensure that the necessary equipment is available for prompt initiation of support critical to a successful neonatal resuscitation, and encourage a debrief to determine if further improvements are necessary for this process. The use of checklists in neonatal resuscitation would therefore seem logical. Checklists have been used in the aviation industry for many years to reduce errors and improve safety of passengers. In the last several years, these tools have begun to be embraced by the medical community to improve patient safety and patient care. They have been found to be useful in helping teams function more effectively, both in simulated environments and in clinical environments. While their use has been shown to yield low compliance when first introduced (Finer and Rich, 2010; Vats et al., 2010), the use of checklists has become a required standard for high-risk interventions such as emergency room traumas and surgical procedures and has been shown to reduce operative mortality (Haynes et al., 2009). Although the initial World Health Organization safe surgery checklist showed a reduction in surgical mortality, the implementation in routine practice in one study failed to show a benefit (Urbach et al., 2014). Some have suspected this is because the implementation of checklists requires some training and a culture of quality as necessary accompanying factors. The most recent American Academy of Pediatrics NRP guidelines recommend the use of checklists for mock codes and related equipment but fall short of recommending them for use in actual resuscitations (NRP, 2016). The use of checklists with a debrief for actual resuscitations provides a mechanism for improving communication and recognizing and resolving problems and should be an essential component of neonatal resuscitation. The use of checklists during neonatal resuscitation is helpful in improving overall communication and allows rapid identification of issues that need to be addressed by institutional leaders (Katheria et al., 2013). We have shown that the introduction of such checklists for neonatal resuscitation has led to improved communication and better overall team function. An example of our institutional checklist is shown in Fig. 24.5. While there needs to be further evaluation of the utility and benefit of checklists for neonatal resuscitation, we encourage the use of institution-specific checklists for neonatal resuscitation teams. The ILCOR recommendations state: “A standardized checklist to ensure that all necessary supplies and equipment are present and functioning may be helpful…” When perinatal risk factors are identified, a team should be mobilized and a team the leader should conduct a pre-resuscitation briefing, identify interventions that may be required, and assign roles and responsibilities to the team members. During resuscitation, it is vital that the team demonstrates effective communication and teamwork skills to help ensure quality and patient safety… It is still suggested that briefing and debriefing techniques be used whenever possible for neonatal resuscitation” (Perlman et al., 2015).

Transition and Resuscitation After birth, blood flow in the umbilical arteries and vein usually continues for a few minutes. The additional blood volume transferred to the baby during this time is known as a placental transfusion. During the first 30 seconds of delayed cord clamping (DCC),

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blood volume in the newborn increases by at least 12 mL/kg (Aladangady et al., 2006; Meyer and Mildenhall, 2012; Sommers et al., 2012; Takami et al., 2012; Katheria et al., 2014). The timing of umbilical cord clamping influences the amount of placental transfusion and subsequent plasma and red blood cell volume of the newborn (Yao et al., 1969; Yao and Lind, 1977). Early clamping may deprive newborns of blood that has an important role in opening the lungs (Jaykka, 1958), increasing cardiac output (Katheria et al., 2015), enhancing lung fluid clearance, and improving oxygen delivery to the newborn’s tissues (Isobe et al., 2000; Jaiswal et al., 2015).

Recommendations and Evidence for Delayed Cord Clamping The established practice of clamping the umbilical cord immediately after the delivery of the newborn was a result of the practice of limiting postpartum hemorrhage, which included immediate cord clamping. However, it was subsequently realized that immediate cord clamping was not required to reduce such hemorrhages. In fact there is no high-level trial-based evidence supporting the use of immediate cord clamping, and such immediate cord clamping has never been subjected to any controlled trial apart from its use as the control group in recent trials of other approaches to allow an adequate placental transfusion. The American College of Obstetricians and Gynecologists recommends a 30–60-second delay before the umbilical cord is clamped in all preterm deliveries, when feasible, to ensure that at-risk newborns receive an adequate placental transfusion (Raju, 2012). The timing for clamping of the umbilical cord after birth is a critical part of the resuscitation of preterm newborns and may have important benefits for perinatal outcomes. Some potential risks that have been raised with DCC, largely derived from term newborn studies, include increased rates of hyperbilirubinemia, polycythemia, and transient tachypnea in the newborn and increased risks of postpartum hemorrhage in the mother. However, several metaanalyses have demonstrated that there were no increases in these morbidities in preterm newborns (Rabe et al., 2012; Backes et al., 2014), and further, DCC does not increase maternal hemorrhage or blood loss (Eichenbaum-Pikser and Zasloff, 2009). In addition, these metaanalyses demonstrated that providing additional placental blood by either DCC or cord milking was associated with less need for transfusion, better circulatory stability, less intraventricular hemorrhage (all grades), decreased mortality, and lower risk of necrotizing enterocolitis (Rabe et al., 2012; Backes et al., 2014). The evidence to date shows that DCC substantively increases hemoglobin and iron stores in early infancy (Andersson et al., 2011). Inadequate iron stores in infancy may have an irreversible impact on the developing brain despite oral iron supplementation. Iron deficiency in infancy can lead to neurologic issues in older children, including poor school performance, decreased cognitive abilities, and behavioral problems. (Mercer and Erickson-Owens, 2012). Andersson et al. (2015) demonstrated that DCC increased scores in the fine-motor and social domains at 4 years of age, particularly in boys.

Cord Milking Cord milking is an alternative to DCC that is used when the cord must be cut immediately for medical reasons, often because the newborn is in need of immediate resuscitation as judged by the clinician overseeing the resuscitation. Cord milking consists of encircling the umbilical cord with the thumb and forefingers,

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• Fig. 24.5  Delivery Room Resuscitation Checklist. DR, Delivery room; ET, endotracheal; FiO2, oxygen concentration; PIP, peak inspiratory pressure; MD, medical doctor; NICO ET, NICO Monitor (PilipsRespironics, Inc.; Wallingford, CT); RN, registered nurse; RT, respiratory therapist.

gently squeezing a short segment of the cord, and slowly pushing the blood through the cord to the newborn’s abdomen three to four times. For newborns born by cesarean there has been a concern that DCC may not provide an adequate placental transfusion. Aladangady et al. (2006) reported lower circulating red cell volume with DCC in newborns born by cesarean compared with vaginal delivery. They also found the duration of delay, up to 90 seconds, increased blood volume in neonates born by vaginal delivery but not cesarean delivery. For neonates born by cesarean, cord milking appears to offer benefits over DCC for 45–60 seconds. Compared with DCC,

cord milking results in greater blood flow to and from the heart, higher hemoglobin levels, and higher blood pressure in neonates born by cesarean (Katheria et al., 2015). Among a smaller number of vaginal births, there was no difference in blood volume between newborns undergoing cord milking and those undergoing DCC.

Breathing During Delayed Cord Clamping Animal studies and one epidemiologic study suggest cord clamping should not occur until the newborn is breathing (Bhatt et al., 2013; Ersdal et al., 2014). One clinical study suggested that DCC

CHAPTER 24  Newborn Resuscitation

results in an inadequate transfusion in depressed newborns who are not breathing during the delay (Nevill and Meyer, 2015). It compared nonbreathing newborns with breathing newborns who underwent DCC and found that nonbreathing newborns had a lower 1-minute Apgar score, were more likely to be intubated, and were at greater risk of chronic lung disease or severe intraventricular hemorrhage (Nevill and Meyer, 2015). However, it is unclear in preterm newborns whether a few gasping breaths or positive pressure ventilation (PPV) is required. Most newborns will tolerate 60 seconds of delay without obvious deterioration. We need more observational data to characterize the need for resuscitation during this critical interval. While hypotonia and pallor may be relevant, most newborns will improve during DCC, and few if any studies have used oximetry during DCC to determine actionable levels. Our own study (Neonatal Resuscitation with Intact Cord, n = 150), where newborns were randomized to undergo DCC alone or receive ventilation during DCC (ClinicalTrials.gov identifier NCT02231411; Katheria et al., 2017), found that ventilation during DCC was feasible but did not lead to any improvements immediately after delivery or reduce neonatal morbidity when compared with simple stimulation during DCC. Our study suggests that more than 90% of preterm newborns will initiate spontaneous breathing during DCC if given some form of stimulation. Thus stimulation to encourage breathing may be as effective as attempting to establish ventilation during DCC in premature newborns. While organizations such as the World Health Organization (2012) have suggested that interventions such as PPV can be started during DCC, our study did not show a measurable benefit from starting interventions when compared with stimulation alone, and larger trials are needed in this area. Clinical trials have demonstrated that both DCC and cord milking in preterm newborns increase cardiac output (Katheria et al., 2015), measures of systemic blood flow (Sommers et al., 2012), and brain oxygen extraction (Takami et al., 2012). Importantly, there is no high-level trial-based evidence supporting the use of immediate cord clamping, which has never been subjected to any controlled trial apart from its use as the control group in recent trials. Providers currently need to evaluate the large body of evidence supporting early placental transfusions (from DCC or cord milking) and compare it with the lack of evidence supporting immediate cord clamping. Providing only warmth and stimulation during DCC may be as good as initiation of respiratory support during DCC, but more studies are needed. Further studies are also needed to determine the optimal type of placental transfusion, the optimal duration of delay, and the use of supportive respiratory interventions; many such studies are ongoing. In the interim, the best available evidence to date along with policy statements from national organizations suggests that DCC should be the standard of care for preterm newborns who do not require resuscitation, and cord milking should be reserved for cases when DCC cannot be performed (Perlman et al., 2015).

Delivery Room Monitoring Assessment Immediately after birth the newborn’s condition is evaluated by general observation as well as measurement of specific parameters. Typically a healthy newborn will cry vigorously and maintain adequate respirations. The color will transition from blue to pink in the first 2–5 minutes, the heart rate will remain in the region

279

of 140–160 beats per minute (bpm), and the newborn will demonstrate adequate muscle tone with some flexion of the extremities. The overall assessment of a newborn who is having difficulty with the transition to extrauterine life will often reveal apnea, bradycardia, hypotonia, and cyanosis or pallor. Following the initial steps of resuscitation, interventions are based mainly on the evaluation of respiratory effort and heart rate, so both must be continually assessed throughout the resuscitation.

Heart Rate Previous NRP recommendations only required a snapshot of the heart rate every 30 seconds to determine whether it fell between two critical cut points (60 and 100 bpm) as defined in the guidelines. Even if the heart rate is being auscultated and manually tapped out by hand, it can be difficult for the leader of the resuscitation to recognize changes quickly. With the inclusion of pulse oximetry for high-risk deliveries, all resuscitation teams can now monitor the heart rate continuously as long as the oximeter is functioning (Kattwinkel et al., 2010). However, the pulse oximeter, while helpful, does not provide a reliable heart rate in the first few minutes of life. Importantly, this is a critical period when decisions, such as the need to begin PPV, must be made. Our group demonstrated that the median time to obtain the heart rate of very low birth weight newborns (G medium-chain acyl-CoA dehydrogenase mutation as second-tier screening. Because this mutation occurs in as many as 90% of individuals with MCADD, this additional analysis of a newborn blood specimen substantially increases the predictive value of the octanoylcarnitine level elevation (Zytkovicz et al., 2001). The fatty acid oxidation disorder is treated by avoidance of fasting with high-carbohydrate, low-fat feedings and, of critical importance, prompt attention to acute illnesses in which vomiting occurs (Yusupov et al., 2010). Carnitine supplementation may be beneficial. Medium-chain triglycerides (i.e., MCT oil) is given for the long-chain disorders VLCADD, LCHADD, and trifunctional protein deficiency. Any infant with a fatty acid oxidation disorder should be evaluated at a metabolic center. Most of these disorders are treatable, but screening enables early diagnosis and genetic counseling for the family even when early treatment may not be effective, such as in neonatal carnitine palmitoyltransferase II deficiency (Albers et al., 2001). Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is likely benign, although before NBS it was considered to be a serious disorder (Waisbren et al., 2008). Organic Acid Disorders Organic acid disorders are a heterogenous group of disorders with a combined frequency of approximately 1 in 50,000 (Zytkovicz et al., 2001). Many of them can be identified through MS/MS screening (see Tables 27.1–27.2). The marker for this disease group, as for the fatty acid oxidation disorders, is an abnormal acylcarnitine pattern. If a screening result suggests an organic acidemia, a metabolic specialist should be consulted immediately. The major organic acid disorders identified in NBS are propionic acidemia, the

methylmalonic acidemias, the cobalamin (vitamin B12) defects, and isovaleric acidemia. The organic acidemias can manifest themselves in the neonatal period with a life-threatening, sepsis-like picture of feeding difficulties, lethargy, vomiting, and seizures. Metabolic acidosis virtually always accompanies this presentation, and hyperammonemia is common. In this situation, protein administration should be discontinued and replaced by the administration of intravenous fluids with high caloric content and carnitine. The hyperammonemia rarely requires specific treatment since control of the organic acid metabolites will almost always result in resolution of the hyperammonemia. The long-term benefits of early diagnosis and treatment for the clinical and neurologic development of individuals affected by an organic acid disorder are under investigation (Dionisi-Vici et al., 2006).

Galactosemia Galactosemia typically manifests itself in the neonatal period as failure to thrive, vomiting, and liver disease (Hughes et al., 2009). Death from bacterial sepsis, usually caused by Escherichia coli, occurs in a high percentage of untreated neonates (Levy et al., 1977). The average incidence of the disorder is 1 in 62,000 (Levy and Hammersen, 1978). Some screening programs use a metabolite assay for total galactose (galactose and galactose 1-phosphate) to detect galactosemia, other programs screen the newborn specimen with a specific semiquantitative enzyme assay for activity of GALT, which is usually undetectable in classic galactosemia, and a few programs use both tests as a primary screen. The enzyme assay identifies only galactosemia, whereas the metabolite assay also identifies other galactose metabolic disorders, such as deficiencies of galactokinase and epimerase. Severe neonatal liver disease and portosystemic shunting caused by anomalies in the portal system can also increase the galactose level. NBS programs that use total galactose as the primary screen usually perform second-tier GALT testing in specimens with elevated galactose level. If the newborn specimen has markedly reduced or absent GALT activity, some screening programs then perform targeted molecular testing for the most frequent mutations associated with galactosemia, particularly gln188arg and asn314asp (Elsas and Lai, 1998). Infants having increased galactose and reduced GALT activity in NBS or those with no detectable activity when only the GALT assay is performed should immediately be seen at a metabolic center. This is particularly important in galactosemia since neonatal sepsis with meningitis, almost always due to E. coli, is a major threat to the galactosemic infant. If the infant is breastfeeding or receiving a regular lactose-containing formula, urine should immediately be tested for reducing substance, and blood should be tested for red blood cell GALT activity and galactose 1-phosphate. Infants with a strongly positive urine-reducing substance finding (3+ or 4+) should also have tests for liver function, including prothrombin time and partial thromboplastin time for coagulopathy, and glucose level for evaluation of hypoglycemia, especially if they are showing clinical signs of galactosemia, such as jaundice, hepatomegaly, poor feeding, and/or lethargy. Breastfeeding or lactosecontaining formula feeding should be discontinued, and appropriate intravenous fluids with glucose should be given as needed. If the urine test is negative for reducing substance, the NBS result is most likely to be false-positive or indicative of a benign GALT variant (e.g., Duarte variant). Nevertheless, urine-reducing substance may be absent in infants with clinically significant variants of galactosemia. Consequently, follow-up testing should be performed

CHAPTER 27  Newborn Screening

for all newborns with an initial positive galactosemia screening result. Markedly increased galactose and normal GALT activity in NBS suggest the possibility of galactokinase deficiency. This disorder produces early-onset cataracts, which are prevented by removal of lactose from the diet. Moderately increased galactose with normal or somewhat reduced GALT activity could indicate uridine diphosphate (UDP)-galactose 4-epimerase deficiency, a largely benign disorder.

Biotinidase Deficiency Biotin recycling is necessary for the maintenance of sufficient intracellular biotin to activate carboxylase enzymes. Biotinidase is a key enzyme in biotin recycling. Lack of biotinidase activity results in reduced carboxylase activities and an organic acid disorder known as multiple carboxylase deficiency (Wolf and Heard, 1991). The clinical features of the disorder are developmental delay, seizures, hearing loss, alopecia, and dermatitis. The developmental delay and seizures usually manifest themselves at 3–4 months of age. Death during infancy has also been reported. Initiation of biotin therapy in early infancy, when the disorder is presymptomatic, seems to prevent all the features of biotinidase deficiency. For this reason, a screening test has been developed and added to NBS in a number of NBS programs throughout the world (Hart et al., 1992). The frequency of newborns identified in these programs has a wide range, from 1 in 30,000 to 1 in 235,000. The average frequency seems to be approximately 1 in 60,000 (Wolf, 2012). With presymptomatic biotin treatment, virtually all identified infants have remained normal. Lysosomal Storage Disorders Lysosomes are organelles required for cellular turnover and contain more than 50 acid hydrolases that catabolize macromolecules. Deficiency of the individual enzyme or a combination of enzymes and transporters can result in accumulation of the substrate and progressive cellular and organ dysfunction. The disease phenotype is a consequence of the type of substrate and its sites of turnover, and severity generally correlates with the amount of residual enzyme activity. The incidence of these disorders as a group is estimated to be 1 in 7700 to 1 in 10,000 births. Direct assay of lysosomal enzymatic activity in dried blood spots by MS/MS or fluorometry techniques is currently feasible for several lysosomal storage disorders (LSDs): Fabry disease, Gaucher disease, Krabbe disease, mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II, Niemann– Pick A/B disease, and Pompe disease (Gelb et al., 2015). Pompe disease and MPS I are the two currently included in the RUSP. Pompe disease, also known as glycogen storage disorder II, is characterized by accumulation of lysosomal glycogen, predominantly in muscles, resulting from the decreased activity of lysosomal acid α-glucosidase (GAA) due to pathogenic variations in the corresponding GAA gene (Leslie and Tinkle, 2013). Pompe disease exhibits a broad spectrum in regard to age of onset, cardiac involvement, and progression of skeletal muscle dysfunction. The severe infantile form manifests itself within the first few months of life and is characterized by severe progressive muscle weakness. Cardiomyopathy is present in the classic form, and without treatment death occurs within the first year of life. Late-onset Pompe disease manifests itself clinically after 1 year of age, often not until adolescence or adulthood, with a slowly progressive myopathy and minimal cardiac involvement. In general, lower GAA levels are associated with earlier onset and greater severity of the disease, although the correlation is not absolute, and diversity among

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individuals with identical GAA genotypes has also been observed, suggesting the effect of other modifying factors (Kroos et al., 2012). In addition to supportive care and nonspecific treatment, enzyme replacement therapy (ERT) is available and should be started as soon as the diagnosis is established. Clinical trials have shown that infants in whom ERT was initiated before the age of 6 months, and before the need for ventilatory assistance, showed improved survival and ventilator-independent survival as compared with untreated historical controls. The overall incidence of Pompe disease is 1 in 28,000, with 28% being the infantile forms. NBS offers the opportunity to detect the infantile forms early (22 days vs 3.6 months by clinical ascertainment) and thus justifies its inclusion in the RUSP. Decreased GAA activity in the screening blood spot should prompt molecular analysis for confirmation. Homozygosity for a “pseudodeficiency” allele c.(1726G>A; 2065G>A) is associated with low GAA activity similar to that seen in patients with Pompe disease but does not cause disease. This genotype, seen in approximately 4% of individuals in the Asian population, will result in false-positive screens in the first-tier enzymatic assays. MPS I is a progressive multisystem disorder with features ranging over a continuum of severity. It is caused by deficiency of the lysosomal enzyme α-L-iduronidase (IDUA) (encoded by the IDUA gene), which leads to an accumulation of glycosaminoglycans (or mucopolysaccharides) within lysosomes of the affected cells (Beck et al., 2014). MPS I is broadly categorized into Hurler syndrome (MPS I H; severe, incidence 1 in 100,000), Hurler–Scheie syndrome (MPS I H/S; attenuated; incidence 1 in 500,000), and Scheie syndrome (MPS I S). Newborns typically appear normal at birth. The severe form manifests itself within the first year of life, and the early findings are quite nonspecific (umbilical hernia, recurrent upper respiratory tract infections). Subsequently, coarsening of the facial features and gibbus deformity of the lower spine may be observed. The severe form is characterized by progressive skeletal dysplasia (dysostosis multiplex) involving all bones, decreased linear growth, and progressive and profound intellectual disability. Corneal clouding and hearing loss are common. Death, typically caused by cardiorespiratory failure, usually occurs within the first 10 years of life. The clinical onset in the attenuated forms is usually between 3–10 years of age. The severity and rate of disease progression span a spectrum, ranging from death in the teens or 20s to a normal life span complicated by disability from progressive joint manifestations and cardiorespiratory disease. Hearing loss and cardiac valvular disease are common. Neurologic and psychomotor involvement are limited in the attenuated forms. Hematopoietic stem cell transplantation (HSCT), considered the standard of care for severe MPS I, increases survival (20–100

• More expeditious >50 miles, ideal efficacy 50–150 miles • Can access less accessible areas • Can potentially be door-to-door

Fixed wing

>100

• Expeditious over long distances, ideal efficacy >150 miles • Can circumvent weather issues • Potential space for family, provider • Ability to pressurize cabin • Requires ground transport to and from airports

Data from Southard PA, Hedges JR, Hunter JG, Ungerleider RM. Impact of a transfer center on interhospital referrals and transfers to a tertiary care center. Acad Emerg Med. 2005;12:653–657.

there are more effective means of communication. Those who have transported or referred patients in systems without centralized access understand the challenges in working through operators, unit clerks, multiple providers, and often multiple services to enable a singular transport. This process is time-consuming and often frustrating for the referring provider, and the time could be better spent in direct assessment and care of the patient. When one is communicating with the transport system, there are key elements that must be considered and appreciated on both sides to initiate and complete a successful patient transfer: 1. Appreciation and recognition of the need for transfer 2. Awareness of appropriate and available transport modality and options 3. Identification of appropriate receiving facility and acceptance by receiving provider 4. Verification of regional and local bed capacity 5. Review of current medical issues 6. Determination of required transport services, including personnel 7. Dispatch of transport team and potential limitations Centralized access through a communication center can allow all those functions to occur simultaneously, enabling more rapid transport response and appropriate involvement of all individuals required for the care of a particular patient (American Academy of Pediatrics Committee on Fetus and Newborn and Bell, 2007; Woodward et al., 2007) (Box 28.1).

Medical Supervision A key requirement for any system is to have appropriately skilled and immediately available medical command physicians (MCPs) (also referred to equally as medical control physicians) (American Academy of Pediatrics Committee on Fetus and Newborn, 2007; Woodward et al., 2007; American Academy of Pediatrics, 2016). An MCP should be literate and expert in the medical area of concern, as well as up to date on transport capabilities. In most cases involving neonatal transport, this provider should be a neonatologist. There may be instances, however, when the referring or receiving physicians may request or desire additional medical expertise. For example, a cyanotic newborn with CHD may be temporarily stabilized by the referring provider and additional medical advice may be provided by the receiving MCP, as well as a partnering cardiac intensive care physician. A communication center can facilitate an initial call in which multiple providers are linked, allowing the highest level of advice to be presented and discussed among providers. These telephone calls should ideally be recorded for quality control and/or for review if verification of

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Features Fewer weather restrictions Door-to-door Well-lit care environment Space for family, providers Efficient in urban, short-range transfers

information is needed and should include the transport personnel so that background information and care plans are communicated directly.

Mode of Transport Once the transport referral has been made and discussions have been started with the MCP, the transport process begins in earnest. A decision on mode of transport is an important consideration at this juncture and is ultimately the responsibility of the referring provider, although it can be appropriately influenced by the MCP. (Table 28.1). In addition to distance from the referring and receiving facilities, which will impact the total transport time, the decision regarding the mode of transport is influenced by several additional considerations when aiming to arrange and dispatch the most appropriate team for a given patient: • Available mode of transport • Staffing and medical expertise of providers involved in each mode • Patient’s current stability and potential illness progression during the projected transport time • Capabilities of referring facility and personnel • Urgency of need for intervention and definitive care of patient • Geography and weather In a study examining the decision-making factors around the mode of transport, Quinn et al. (2015) found that the decision to activate a helicopter versus a ground unit was made in the face of not only prolonged distance (>45–60-minute drive time) but also the presence of perceived high-risk clinical conditions, specifically neurovascular and respiratory concerns, even more so than blood pressure or heart rate. Currently, there are guidelines but no national absolute criteria or standards to direct the choice of ground versus air transport. Each modality has its own risks and benefits. First, with both air

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and ground transfer, concerns include potential physiologic stress and discomfort experienced by the neonate secondary to stimuli such as vibration and noise (Schierholz, 2010; Sittig et al., 2011; Bouchut et al., 2011; Harrison and McKechnie, 2012; Karlsson et al., 2012; Prehn et al., 2015). Therefore adjuncts to minimize the stress and discomfort, such as gel mattresses and earmuffs, should be used as much as possible. Air transport can also present specific stressful stimuli such as gravitational forces during acceleration and deceleration, temperature variations, and decreased humidity with altitude and introduces issues related to altitude physiology that can affect patients with respiratory issues or air trapping as well as air-containing equipment (e.g., endotracheal tube cuffs, laryngeal mask airways) ( Woodward and Vernon, 2002; Wilson et al., 2008; Woodward et al., 2006; Schierholz, 2010). Dalton’s law recognizes that ambient oxygen partial pressure decreases as altitude increases; therefore there may be a need for pressurization and augmentation with increased fraction of inspired oxygen. Boyle’s law states that as altitude increases, the volume of a gas also increases, as barometric pressure is inversely related to the volume of the gas. Thus consequences of this law are potentially a serious issue for patients with an enclosed gas collection, such as a simple or developing pneumothorax or pneumatosis in suspected cases of necrotizing enterocolitis. Secondly, weather and physical distance can make each mode of transport more or less accessible or reasonable at a given time. For instance, while ground transport may be more readily available than air transport because of fewer weather constraints and an increased number of vehicles, the overall transport time may be too long given the clinical needs of the patient. Finally, each mode of transport has occupancy limitations associated with select vehicles, especially rotary air transport. These limitations can preclude extra passengers such as parents or family members or potentially crew members if weight and balance is an issue.

Transport Personnel, Education, and Team Composition Awareness of the capabilities of the transport system and of the personnel involved is imperative in decisions regarding the mode of transport. Although it is ultimately the responsibility of the referring physician to identify the appropriate mode and personnel for transport, per the federal Emergency Medical Treatment and Active Labor Act (EMTALA), opportunities exist for tertiary care and referral centers to help inform the referring providers regarding optimal transport planning and use (Bolte, 1995; Woodward, 1995). In general, issues influencing transport decisions include the patient’s current level of care, urgency for a different level of medical capability or equipment, current provider capabilities, stability of the patient, options available to the provider and patient, and efficiency and quality of the transport process. Ideally, these issues are key determinants of appropriate transfer; however, referring providers are often overwhelmed by the severity or acuity of the patient, and their primary desire may be to have the patient removed from their facility as quickly as possible. The providers may focus on a transfer process based solely on the speed of transport rather than the quality of care. It is imperative for the receiving and tertiary care centers to educate the referring providers regarding the importance of stabilization, initiation and quality of the primary response, transport options, and definitive care to maximize patient outcome. When examining the transfer of patients, providers should

ask a simple question: Are we trying to deliver the patient to tertiary care, or are we trying to deliver tertiary care to the patient? In most high-functioning transport and referral centers, the latter is true. The referring physician should expect to have tertiary care advice and direction delivered at the moment of the referral call and continued throughout the transport process (Woodward, 1995; American Academy of Pediatrics Committee on Fetus and Newborn and Bell, 2007; Woodward et al., 2007). When considering the transport team composition, it is important to consider the quality of the personnel, their expertise and experience, and their ability to work in the transport environment (King et al., 2001, King and Woodward, 2002a; King et al., 2007). There are many variations of transport teams in the United States and abroad (Karlsen et al., 2011). These teams can be composed of a combination of physicians, nurse practitioners, nurses, respiratory therapists, paramedics, and other healthcare providers. Regardless of the formal educational background of an individual, there are several criteria that must be met to be optimally effective in the transport environment. First, the provider must have adequate certification, be licensed for the care he/she delivers, and be able to provide the assessments and interventions that a patient currently or potentially requires during the transport process. For example, a neonatal retrieval service must be able to manage acute and critical airways in the neonatal population, both at a referring hospital and during the transport. While transport team providers might not be credentialed to provide certain skills within their home hospital (i.e., intubation), they have been certified to provide them in the ambulance environment. In general, this must be done under the auspices of a physician’s care, which may be from an accompanying physician or via online medical control (real-time medical advice during the transport process) or protocolbased care (off-line medical control). It is important to recognize that the transport time frame is somewhat limited; therefore the personnel may not need to have the longitudinal or differential diagnosis expertise of a fully trained neonatologist. However, these personnel must have the acute care assessment abilities and intervention skills of an experienced neonatal expert. From the transport and pediatric literature, patient outcomes are improved with specialty providers. While multiple studies have examined this particular issue (Mullane et al., 2004; Belway et al., 2006; Borrows et al., 2010; Kuch et al., 2011), the most compelling is the study by Orr et al. (2009), which examined transport by variable providers within the same system. This study compared outcomes in patients whose care was delivered by specialized pediatric critical care teams with those whose care was delivered by general providers. Both teams had the same medical command oversight, equipment, and modalities. Patient outcomes were worse for those whose care was not delivered by specialty teams and was much improved for those whose care was delivered by specialty teams. While the study by Orr et al. and studies by others are compelling, a recent Cochrane review that focused specifically on neonatal specialty teams (Chang et al., 2015) concluded that in the absence of randomized controlled studies there is not good evidence to refute or support the use of neonatal specialty teams for high-risk neonates. Evidently, specialty teams and patient outcomes is an area for ongoing investigation. In addition to training the transport personnel, MCPs should understand the opportunities and limitations of the transport services, the environment, and the risks and challenges that referring personnel can potentially encounter with situations and patients who exceed their own or their facility’s management abilities. It is imperative that MCPs have clear and efficient communication,

CHAPTER 28  Neonatal Transport

not only with referring providers and those from different disciplines but also within the transport team.

Quality Improvement Throughout medicine, there is an increasing focus on measuring and improving the quality of care provided across all healthcare domains and patient experiences. Transport medicine offers an opportunity for potential quality improvement activities within the inpatient arena, in the transport system, and at the referring facilities (Chen et al., 2005; Browning Carmo et al., 2008; Lim and Ratnavel, 2008; McPherson et al., 2008; Ramnarayan, 2009). While there are guidelines of care and process recommendations such as those provided through the American Academy of Pediatrics and the Commission on Accreditation of Medical Transport Services, formal national transport benchmarks or standard quality-of-care metrics are still evolving. A consensus document on behalf of the American Academy of Pediatrics Section on Transport Medicine was recently published that offers 12 core quality metrics for neonatal and pediatric transport (Schwartz et al., 2015). The proposed neonatal and pediatric transport national benchmark and quality metrics are as follows: 1. Unplanned dislodgement of therapeutic devices 2. Verification of tracheal tube placement 3. Average mobilization time of the transport team 4. First-attempt tracheal tube placement success 5. Rate of transport-related patient injuries 6. Rate of medication administration errors 7. Rate of patient medical equipment failure during transport 8. Rate of CPR performed during transport 9. Rate of serious reportable events (http://www.qualityforum.org/ Topics/SRE/List_of_SREs.aspx) 10. Unintended neonatal hypothermia on arrival at destination 11. Rate of transport-related crew injury 12. Use of standardized patient care handover The authors propose that these metrics serve as benchmarks and help guide individual program quality improvement. Details of their recommendations can be accessed at http://www.aap-sotm.org. Neonatal and pediatric airway management may be one of the most important aspects of transport clinical care and historically is one of the more challenging areas for emergent and prehospital management. Examples of quality-based investigations reflect these challenges and provide information to guide improvements. Bigelow et al. (2015) retrospectively assessed first-pass intubation success for neonatal and pediatric patients across nine transport programs over a 6-month period. The overall success rate was 64%, with a range of 35%–87%, but was highest for teams that had live-patient training for initial competency and lowest for those using simulation alone. Smith et al. (2015) considered risk factors for intubation failure among neonatal and pediatric specialty teams and found higher rates of intubation failure for neonates compared with pediatric patients, especially for the smallest neonates necessitating the use of tube sizes of 2.5 mm or less. Additional risk factors for failure were the use of uncuffed tubes and the failure to use sedation and the lack of neuromuscular blockade. Quality improvement activities in the transport domain are diverse and range from assessment of the transport process by review of recorded calls to the monitoring of intubation success and vital signs in transport to improving communication through standard handovers (Weingart et al., 2013). However, this glimpse into facility/provider medical sophistication and capability is one that is privileged and should be used to identify educational

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opportunities for all providers involved rather than used as a judgmental review. Education by receiving physicians and transport teams can have a significant effect on the quality and outcome of patient care and the volume of future referrals. Ideally, once a referral call is made, a receiving physician or MCP will direct the care so that the job of the transport team is to verify that an appropriate working diagnosis has been made and adequate stabilization has been achieved. Systems that do not gather adequate information or offer appropriate advice, or in which the referring facilities do not follow that advice or choose not to perform needed interventions, can put the patient at risk by delaying potentially necessary interventions, prolonging the transport process, and delaying delivery of definitive care. The transport team that has invested several hours at a bedside stabilizing a newborn with medical or surgical issues may be spending time in a facility that is not ideal, has a limited number of skilled personnel, and has minimal backup, thus prolonging the transport process, delaying definitive care, and potentially putting that individual patient and the transport team at risk (Chen et al., 2005; Haji-Michael, 2005). Furthermore, during this prolonged stabilization time, the entire system becomes at risk because the valuable resource of specialized neonatal transport personnel is not available for another patient. Ideally, care delivery would be the same at referral and receiving centers, and the development of practice guidelines can help in this regard. Guidelines that are evidence based, developed by regional and local experts, and disseminated to referring centers and transport teams will help standardize and promote consistent care across variable locations. It is necessary, however, to assess and reassess the quality of the guidelines and the competency of their use to ensure optimal results. Even in the best of hands, near-miss or realized adverse events may happen. It is clear that identification of those events, discussion with families (where appropriate), and root cause analysis are imperative. Several studies have examined adverse events in transported patients. Van den Berg et al. (2015) looked at adverse events over 13 years with their neonatal transport team in northern Sweden. They found that such events had differing significance (53% low risk to 11% high or extreme risk), were common, and were often related to transport logistics and equipment failure. Ligtenberg et al. (2005) noted that one-third of patients had an adverse event, and 50% of adverse events resulted from the advice of the MCP not being followed. Of that group, 70% of events were avoidable and 30% involved logistical issues. In a review of the London Neonatal Transfer Service, Lim and Ratnavel (2008) noted that 36% of their patients had one or more adverse events and that two-thirds of those were due to human error. Half of the events occurred before the team arrived at the referral center and were due to patient preparation and communication issues.

Transport Administration As a hospital develops and optimizes a neonatal transport program, experts in transport medicine are integral to the success of the program (American Academy of Pediatrics Committee on Fetus and Newborn and Bell, 2007; Woodward et al., 2007). A quality medical director and program director, often a nurse or respiratory therapist, are essential for understanding the potentially complicated and challenging environment of transport medicine. These leaders should be instrumental in identifying expectations, roles, and responsibilities for the entire transport process, including oversight of the communication center and developing and disseminating referral center expectations.

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The responsibilities of the referring center when transferring patients are to: • Stabilize and prepare the patient before transport. • Make an appropriate decision to transfer the patient. • Choose an appropriate transport process and destination. • Obtain family consent for transport, including the mode and receiving facility. • Discuss and initiate a plan for stabilization with the medical command physician. • Communicate clearly when suggested interventions are beyond the scope of the referring center or cannot be done. • Be present and participate in the transition of care to the transport team and the receiving service. In turn, there are also clear expectations of the receiving center and transport team. • Immediate availability for patient care consultation • Able and qualified to provide clear and concise recommendations • Quick determination if able to accept the patient for transfer • Ensure that receiving facility staff are prepared for both patient and transport team arrival. • Document interaction with and recommendations to the referring facility. Most importantly, the team needs to ensure that appropriate skills and therapeutics are available and delivered throughout the process, from the referral call through definitive placement, and ensure seamless transition at each point of care. The team needs to communicate well with the patient’s physicians and document their advice, interventions, and activities in a clear, concise fashion to enable appropriate patient care and provide protection for the transport service.

Transport Safety Safety of the transport system and its providers is paramount and must be assessed and ensured before any patient is transported. Vehicles must be safe and meet the standards for air or ground transport; the personnel must be trained and skilled in the care of neonates, licensed, and competent; and the patients must be managed in the most appropriate and professional fashion. In addition, the logistics of travel must include a safe environment, including helmets and fire-retardant suits for those who fly in helicopters, three-point restraints, and appropriate ambulance seating arrangements. Providers should not put themselves at risk by being unrestrained or being in an area where unsecured debris or inappropriately placed equipment may cause harm to them or the patient. Adherence to all rules and regulations of air and ground travel is essential (Clawson, 2002; King and Woodward, 2002b; Levick, 2006; Greene, 2009; National Highway Traffic Safety Administration, 2009). It is important to recognize that there are risks with both air and ground transport. The air transport industry saw a spike in tragic and fatal air accidents (Greene, 2009; National Transportation Safety Board Accident Database, 2009). This increase caused the industry, and the US government, to investigate these incidents and offer recommendations to improve transport safety (Fact Sheet –FAA Initiatives to Improve Helicopter Air Ambulance Safety, 2014; Flight Safety Foundation/Aerosafteyworld, 2008). Requirements such as duty hours for pilots, weather restrictions, flight under instrument flight rules with terrain avoidance equipment, and night vision goggles can help to minimize transport risk. While ground ambulances are used much more frequently and the risk of injury and death is evident, the fatality rate is lower in ambulance accidents than it is in aircraft accidents (King and Woodward,

2002b; Becker, 2003; Becker et al., 2003). Many systems do not allow ambulances to exceed posted speed limits and allow them to use lights and sirens only as a way to identify an emergency response not to enable the vehicle to circumvent or ignore standard traffic laws (Clawson, 2002). Appropriate equipment for ambulances is required as well, and the most recent joint statement by the American College of Surgeons Committee on Trauma and the American Academy of Pediatrics regarding appropriate equipment for ambulances should be reviewed by the providers of all transport systems (American Academy of Pediatrics, American College of Emergency Physicians, American College of Surgeons, et al., 2014). One challenge for transport teams is that differentiation of medical resources, such as a neonatal specialty team, likely means that there may be a scarcity of resources and a potential need to ration those resources. It is possible to develop teams with a variety of personnel with complementary cognitive and procedural skill sets and work toward appropriate triage of transport requests to ensure the optimal level of onsite patient care and safe transport. There have been multiple attempts to develop triage tools for pediatric and neonatal care providers, including the Mortality Index for Neonatal Transport, the Modified Clinical Risk Index for Babies, the Risk Score for Transported Patients, and the Transport Risk Index of Physiologic Stability (TRIPS) (Lee et al., 2001; Broughton et al., 2004a, 2004b; Markakis et al., 2006). Notably, TRIPS is a validated tool that can be calculated in a single assessment and has been shown to correlate with NICU mortality. The original authors of TRIPS recently validated TRIPS-II, the application of TRIPS over 12–24 hours after NICU admission, and found it correlates with illness severity not only at admission but also up to 24 hours (Lee et al., 2013). Given the simplicity and ease of use, TRIPS and possibly TRIPS-II are examples of scoring tools that can be applied in both the transport environment and the hospital environment reflecting clinical deterioration or improvement over time.

Family-Centered Care Transport team research has shown that family-oriented care, as in other areas of health care, is an important component of transport (Woodward and Fleegler, 2000, 2001; Granrud et al., 2014; Mullaney et al., 2014; Joyce et al., 2015; American Academy of Pediatrics, 2016). Families who have been formally surveyed appreciate the opportunity to participate in the care of their child and express increased stress and anxiety when they do not accompany their child during transport (Mullaney et al., 2014; Joyce et al., 2015). In neonatal transport, however, there are times when there are two patients who may require care in two disparate locations. A mother who has had a cesarean delivery and has delivered an acutely ill neonate who requires transfer to a specialty pediatric facility with neonatal intensive care capability is one such example. Transport teams should be sensitive to the challenges and opportunities for the family members and include them in the process when possible. It is evident that when parents attend or accompany transport team members during critical care transports, they are there not to assess the medical skill set of the provider but to provide support to their child. It is also a great opportunity for the transport team to demonstrate to the family that their patient is in focused, professional, caring, and capable hands.

Medical Legal Issues There are many medical legal issues in transport medicine, as elsewhere in the medical system (Williams, 2001; Woodward,

CHAPTER 28  Neonatal Transport

2003; Hedges et al., 2006; Fanaroff, 2013; American Academy of Pediatrics, 2016). The Health Insurance Portability and Accountability Act is a required component of transport planning and delivery. Discussion of patients should not happen in a public area or via public communication airways, where patient-specific information could be overheard. As noted earlier, a requirement of EMTALA is that the referring physician choose the appropriate mode of transport and ensure that the transport process and receiving hospital are appropriate for the particular patient. Patients should not be transferred if they are unstable and the ability to further stabilize them is available at the initial site of care. If a patient must be transferred for care while in an unstable condition—a frequent scenario for critically ill patients who need care not available at the referring institution—consent must be obtained from the family, which acknowledges their understanding of the potential risks and benefits of the process. In practice, there are often patients in an unstable condition who are transferred from lower to higher levels of care because the level of care that can be provided at the referring center is not optimal for the child. This reason is appropriate for transfer as compared with transfer of acutely unstable patients because of financial or other economic incentives. The medical liability for transport is a shared process. Before the referring center contacts a receiving facility or transport team, the entire medical responsibility lies with the referring provider. Once the receiving team has accepted the patient and offered advice, medical liability becomes a shared process. The referring physician maintains most of the liability, as well as medical control of the patient, throughout the process until the transport team has left the referring hospital. It is important to recognize that most transport teams and personnel do not have privileges at referring hospitals and are working under the guidance and supervision of the referring physician team. Transport teams that act independently, or referring providers who are not available when the transport team arrives, put not only the patient but also the referring provider and transport team at risk. There will be times, however, when there is disagreement regarding the optimal care to be delivered. This situation can be challenging, and it must be handled appropriately. It is never appropriate to have obvious provider conflict occur at a patient’s bedside in front of family members. The appropriate way to handle a situation that cannot be easily mitigated is to involve the MCP with a telephone call to the referring physician in a discussion at a peer-to-peer level. Transport teams have been known to comply with the wishes of the referring providers to not perform advanced procedures at the referring hospital, only to perform those procedures in the ground or air ambulance, which is a much less desirable location. Ideally, all disagreements and considerations of different therapies should be discussed in a collegial fashion. As noted previously, documentation of all information received and advice offered is imperative. If there is a review or there are challenges regarding the care delivered before or during transport, clear and appropriate documentation should stand alone as an excellent defense. In addition, many centers use recorded (i.e., digital, tape, other retrievable recording process) intake and advice lines; this is another way to review, educate, and ensure that appropriate information is delivered in an effective communication style. The use of recorded lines with frequent review, for educational and quality assurance purposes, can be invaluable. Review with legal advisors can help define the length of time the recorded materials should be maintained for quality improvement or patient record addendum.

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Patient Care During Transport The primary clinical goals for any neonatal transport include, but are not limited to, the following and should be established during the initial stabilization phase before departure from the referring facility and maintained until handover at the receiving facility: • Secure and patent airway • Adequate ventilation and oxygenation • Thermoregulation, especially for premature neonates, goal 36°C –37°C (except as indicated for hypoxic–ischemic encephalopathy) • Normoglycemia, goal glucose level 50–200 mg/dL • Adequate blood pressure and perfusion • Appropriate condition-specific care such as for myelomeningocele A team’s ability to achieve these care goals may be impacted by the patient’s clinical status but will also depend on the team’s preparedness and skill and experience caring for critically ill neonates. Therefore the general approach to any neonatal transport includes ensuring the availability of appropriate equipment, such as an isolette and endotracheal tubes for the smallest premature neonates, that there are skilled team members who can optimally care for a sick neonate, that there are appropriate medications for specific situations such as prostaglandin E1 (PGE1), and that there is smooth communication with the MCP.

Extreme Prematurity and the Limits of Viability Of the approximately 4 million live births that occur annually in the United States, approximately 10% are preterm ( adults) Production of proinflammatory cytokines (sepsis, anaphylaxis, hypoxic tissue injury, tissue ischemia, ischemia–reperfusion, soft tissue trauma, extracorporeal membrane oxygenation) Increased capillary surface area Vasodilation

Conditions Associated With Decreased Lymphatic Drainage Decreased muscle movement Neuromuscular blockade and/or heavy sedation Central and/or peripheral nervous system disease Obstruction of lymphatic flow Increased central venous pressure Scar tissue formation (bronchopulmonary dysplasia) Mechanical obstruction (dressings, high mean airway pressure in mechanically ventilated newborns)

improvements in the cardiovascular status compared with 4.5% or 5% albumin infusion, the topic remains controversial. Even in the presence of hypoalbuminemia, when sick neonates are treated with frequent albumin boluses, much of the infused albumin rapidly leaks into the interstitium. This creates a vicious cycle of intravascular volume depletion and edema formation, resulting in vasoconstriction and disturbances in tissue perfusion and cellular function, exacerbating impairments in the regulation of extracellular volume distribution. If the cycle is not interrupted, anasarca will develop, which is usually associated with an extremely poor prognosis. In summary, the sick neonate has limited capacity to maintain appropriate intravascular volume and to regulate the volume and composition of the interstitium, and thus high vigilance is required by the caretaker in appropriately managing intravascular volume, including avoiding routine use of albumin in the critically ill neonate (Uhing, 2004). Regulation of the Extracellular Solute and Water Compartment

The osmolality of the extracellular compartment is tightly maintained within 2% of the osmolar set point, which lies between 275 and 290 milliosmole (mOsm) (Robertson and Berl, 1986). Blood pressure and serum sodium concentration (i.e., the main

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contributor to osmolality under homeostatic conditions) are monitored by baroreceptors and osmoreceptors respectively. The effector limb of the regulatory system consists of the heart, vascular bed, kidneys, and intake of fluid in response to thirst. The inability of critically ill term and preterm neonates to maintain fluid balance by responding to thirst places increased importance on caregiver management of fluid administration. By regulating the function of the effector organs, several hormones play a role in the control of the extracellular compartment, including the renin–angiotensin– aldosterone system, vasopressin, ANP, brain (B-type) natriuretic peptide (BNP), bradykinin, prostaglandins, and catecholamines. Effective regulation of the extracellular compartment and intravascular volume also depends on intact cardiovascular function and capillary endothelium integrity (Robertson and Berl, 1986). For example, under physiologic conditions, an increase in the extracellular volume is reflected by an increase in the circulating plasma volume, leading to increased blood pressure and renal blood flow. The ensuing increase in glomerular filtration and urine output returns the extracellular volume to normal. In critically ill neonates, however, the capillary leak and reduced myocardial responsiveness resulting from immaturity and underlying pathologic conditions limit the increase in the circulating blood volume when extracellular volume expands. Thus especially in sick preterm neonates, blood pressure may rise only transiently (Lundstrøm et al., 2000), and renal blood flow may remain low after volume boluses as fluid rapidly leaks into the interstitium. Inappropriate central regulation of vascular tone results in vasodilatation, further decreasing effective circulating blood volume and compromising tissue perfusion; this leads to impaired gas exchange in the lungs, resulting in hypoxia with further increases in capillary leak. Unless it is interrupted by appropriate therapeutic measures, a vicious cycle with further deterioration readily occurs in the sick neonate.

Maturation of Organs Regulating Body Composition and Fluid Compartments The heart, kidneys, skin, and endocrine system play the most important roles in the regulation of ECF (and thus intracellular fluid) and electrolyte balance in the neonate. Immaturity of these organ systems, especially in infants with very low birth weight (VLBW), results in a compromised regulatory capacity, which must be noted when one is estimating daily fluid and electrolyte requirements in these patients. Maturation of the Cardiovascular System

There is a direct relationship between gestational maturity and the ability of the neonatal heart to respond to acute volume loading (Baylen et al., 1986). The blunted Starling response of the immature myocardium results from its lower content of contractile elements and incomplete sympathetic innervations (Mahony, 1995). Because central vasoregulation and endothelial integrity are also developmentally regulated (Gold and Brace, 1988; Bauer, 2011), an appropriate effective intravascular volume is seldom maintained in the critically ill preterm neonate. Since regulation of the extracellular volume requires the maintenance of an adequate effective circulating blood volume, the immaturity of the cardiovascular system contributes to the limited capacity of sick preterm neonates to effectively regulate the total volume of their extracellular compartment. Maturation of Renal Function

The kidney has a crucial role in the physiologic control of fluid and electrolyte balance. It regulates extracellular volume and

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PART V I I I  High-Risk Newborn Care

0

Transepidermal water loss (g/m2 per hr)

3

)

ys

60 50

Po

20

a at

n

st

30

ge

la

7

40

a (d

21

10 0 26

28

30 32 34 36 Gestational age (weeks)

38

40

• Fig. 30.4  Transepidermal water loss in relation to gestational age during the first 28 postnatal days in

newborns who are appropriate for their gestational age. There is an exponential relationship between transepidermal water loss and gestational age, the water loss being higher in preterm newborns than in term newborns. Transepidermal water loss is also significantly affected by postnatal age, especially in the immature preterm newborn. The measurements were performed at ambient air humidity of 50% and with the newborns calm and quiet. (From Hammarlund K, Sedin G, Stromberg B. Transepidermal water loss in newborn infants. VIII: relation to gestational age and post-natal age in appropriate and small for gestational age infants. Acta Paediatr Scand. 1983;72:721–728.)

osmolality through the selective reabsorption of sodium and water respectively. Immaturity of renal function renders preterm neonates susceptible to excessive sodium and bicarbonate losses (Modi, 2004; Brewer, 2011). In addition, the inability of the preterm neonate to respond promptly to a sodium or volume load results in a tendency toward extracellular volume expansion with edema formation. Because prenatal steroid administration accelerates maturation of renal function (van den Anker et al., 1994), preterm neonates exposed to steroids in utero have a better capacity to regulate their postnatal ECF contractions. During the first few weeks postnatally, hemodynamically stable but extremely immature infants produce dilute urine and may develop polyuria because of their renal tubular immaturity. As tubular functions mature, their concentrating capacity gradually increases from the second week to the fourth week of postnatal life. However, it takes years for the developing kidney to reach the concentrating capacity of the adult kidney (Linshaw, 2011). Maturation of the Skin

Although the epidermis of term neonates is well developed and cornified, in extremely immature neonates it consists of only two or three cell layers (Chu and Loomis, 2011). The absence of an effective barrier to the diffusion of water increases TEWL in the immature neonate. TEWL through immature skin can result in early postnatal hypertonic dehydration, with rapid changes in intracellular volume and osmolality. In many organs, especially the brain, these abrupt changes can result in cellular dysfunction and ultimately cell death. Gestational age, postnatal age, the pattern of intrauterine growth, and environmental factors (e.g., humidity and temperature) affect transepidermal free water loss (Fig. 30.4).

Postnatal skin cornification occurs rapidly, but full maturation of the epidermis does not occur until 2–3 weeks of age (Cartlidge, 2000). Chronic intrauterine stress (Hammarlund et al., 1983) and prenatal steroid treatment (Aszterbaum et al., 1993) also enhance maturation of the skin. Maturation of End-Organ Responsiveness to Hormones Involved in the Regulation of Fluid and Electrolyte Balance

Several hormones directly regulate the volume and composition of the extracellular compartment by altering renal sodium and water excretion and by inducing changes in systemic vascular resistance and myocardial contractility. These include the renin– angiotensin–aldosterone system, vasopressin, ANP, and BNP. Other hormones, including the prostaglandins, bradykinin, and prolactin, modulate the actions of many of the regulatory hormones. Renin–Angiotensin–Aldosterone System.  Decreases in renal capillary blood flow stimulate renin secretion from the juxtaglomerular cells of the kidney, which in turn catalyzes the conversion of angiotensinogen to angiotensin I. Angiotensin-converting enzyme hydrolyzes angiotensin I to angiotensin II, which can then bind to the cell membrane–bound receptors AT1 and AT2 (Sequeira et al., 2011). Angiotensin induces vasoconstriction, increased tubular sodium and water reabsorption, and the release of aldosterone (Sequeira et al., 2011). Aldosterone increases potassium secretion and further enhances sodium reabsorption in the distal tubule; therefore the primary function of this system is to protect the volume of the extracellular compartment and maintain adequate tissue perfusion (Bailie, 1992). However, its effectiveness in the neonate is somewhat limited by the decreased responsiveness of the immature kidney to the sodium-retaining and water-retaining

CHAPTER 30  Fluid, Electrolyte, and Acid–Base Balance 

effects of these hormones (Sulyok et al., 1985; Feld et al., 2011). Vasodilatory and natriuretic prostaglandins generated in the kidney (Gleason, 1987) are the main counterregulatory hormones balancing the renal actions of the renin–angiotensin–aldosterone system. Therefore when prostaglandin production is inhibited by indomethacin, the unopposed vasoconstrictive and sodium-retentive actions of the activated renin–angiotensin–aldosterone system contribute to the development of the drug-induced renal failure in the preterm neonate (Gleason, 1987; Seri, 1995; Seri et al., 2002). Vasopressin.  Vasopressin (antidiuretic hormone) regulates the osmolality of the extracellular compartment and directly effects vascular tone through the V1a and V2 receptors. Vasopressin selectively raises free water reabsorption through the upregulation of aquaporin-2 water channels in the collecting duct, resulting in blood pressure elevation (Elliot et al., 1996; Linshaw 2011). Although it appears that the developing kidney is less sensitive to circulating vasopressin, plasma levels of vasopressin are markedly elevated in the neonate, especially after vaginal delivery, and its cardiovascular actions facilitate neonatal adaptation (Pohjavuori et al., 1985; Linshaw, 2011). The high vasopressin levels are in part also responsible for the diminished urine output of the healthy term neonate during the first day after birth. Under certain pathologic conditions, the dysregulated release of, or the end-organ unresponsiveness to, vasopressin significantly affects renal and cardiovascular functions and electrolyte and fluid status in the sick preterm and term neonate (Svenningsen et al., 1974). In the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), an uncontrolled release of vasopressin occurs in sick preterm and term neonates, with resulting water retention, hyponatremia, and oliguria. In the syndrome of diabetes insipidus, the lack of pituitary production of vasopressin or renal unresponsiveness to vasopressin results in polyuria and hypernatremia. Atrial Natriuretic Peptide.  Via its direct vasodilatory and renal natriuretic actions, the hormone ANP regulates the volume of the extracellular compartment in the fetus and neonate in a fashion opposite to that of the renin–angiotensin–aldosterone system (Seymour, 1985; Needleman et al., 1986; Solhaug and Jose, 2011). ANP has a direct inhibitory effect on renin production and aldosterone release (Christensen, 1993). The stretch of the atrial wall caused by an increase in the circulating blood volume is the most potent stimulus for ANP release. Plasma levels are high in the fetus (Claycomb, 1988) and along with BNP, ANP likely plays a role in cardiac development (Das et al., 2009). There are a few specific conditions in which the actions of ANP are directly relevant for the neonatologist. For example, the hormone is involved in the regulation of both the fluid shifts during labor (Bauer, 2011) and the extracellular volume contraction during postnatal transition (Kojima et al., 1987; Tulassay et al., 1987; Rozycki and Baumgart, 1991; Ronconi et al., 1995). Furthermore, the oliguric effects of positive end-expiratory pressure ventilation are due in part to a decrease in ANP secretion (Christensen, 1993) along with the enhanced release of vasopressin (El-Dahr and Chevalier, 1990). Brain (or B-Type) Natriuretic Peptide.  BNP is released from the ventricular myocardium in response to increases in wall tension. Similarly to ANP, BNP causes natriuresis, diuresis, and vasodilatation, while inhibiting the renin–angiotensin–aldosterone system (Kojima et al., 1989; Gemelli et al., 1991; Holmes et al., 1993). Compared with ANP, BNP and the inactive N-terminal fragment of BNP (NT-proBNP) demonstrate longer half-lives and thus may be more useful clinical biomarkers as their levels are relatively more

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stable over time (Vijlbrief, 2012). NT-proBNP is renally excreted, and renal function should be considered when one is interpreting levels (Breuer, 2007). BNP levels increase rapidly after birth, with the levels by the end of the first day up to 20-fold higher than those at birth (Yoshibayashi et al., 1995; Mir et al., 2003), and they correlate with the downward trend in pulmonary arterial pressure, diuresis, and renal maturation in the days after birth, unlike ANP levels (Ikemoto et al., 1996). By causing vasodilatation and diuresis, high levels of BNP play a critical role in the hemodynamic transition of the fetus. BNP levels continue to fall during the first week after birth (Koch et al., 2003; Mir et al., 2003). The usefulness of measuring BNP levels is limited by the variability of levels in the first few days after birth as well as the variety of assays available to measure BNP levels. Its utility may ultimately lie in repeated measurements in the same patient over time with the same assay in order to follow trends. Prostaglandins.  Prostaglandins have a well-documented, counterregulatory role for the renal vascular and tubular effects of renin–angiotensin–aldosterone and vasopressin (Bonvalet et al., 1987). The inhibition of prostaglandin synthesis by indomethacin results in clinically important and sometimes detrimental renal vascular and tubular effects in the preterm neonate (Mercanti et al., 2009). Importantly, ibuprofen demonstrates fewer side effects than indomethacin on renal and mesenteric blood flow (Mercanti et al., 2009). How prostaglandins modulate the effects of the other regulatory hormones of neonatal fluid and electrolyte homeostasis is less well studied. Prolactin.  Prolactin plays a permissive role in the regulation of fetal and neonatal water homeostasis (Coulter, 1983; Pullano et al., 1989). High fetal plasma prolactin levels contribute to the increased tissue water content of the fetus. Postnatal prolactin levels remain high in the preterm neonate until approximately the 40th postconceptional week (Perlman et al., 1978). Low levels have been associated with increased risk of developing respiratory distress syndrome (RDS) (Gluckman et al., 1978; Hauth et al., 1978; Smith et al., 1980).

Management of Fluid and Electrolyte Homeostasis General Principles of Fluid and Electrolyte Management Fluid and electrolyte management is the cornerstone of neonatal intensive care, and appropriate management requires an understanding of the previously outlined physiologic principles and careful monitoring of key clinical data. Requirements vary substantially from infant to infant and in the same infant over time; therefore fluid prescription must be individualized and frequently reassessed. The primary goals are to maintain the appropriate ECF volume, ECF and intracellular fluid osmolality, and ionic concentrations. Assessment of Fluid and Electrolyte Status

Maternal conditions during pregnancy, drugs and fluids administered to the mother during labor and delivery, and specific fetal and neonatal conditions all affect early fluid and electrolyte balance. Excessive administration of free water or oxytocin use in the mother can result in hyponatremia in the neonate. Maternal therapy with indomethacin, angiotensin-converting enzyme inhibitors, furosemide, and aminoglycosides can all adversely affect neonatal renal function. A newborn’s history of oligohydramnios or birth asphyxia may also alert the clinician to the possibility of abnormal renal function. In young neonates, altered skin turgor, sunken anterior

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fontanel, and dry mucous membrane are not sensitive indicators of dehydration, but tachycardia, hypotension, metabolic acidosis, and oliguria may be seen when intravascular volume is moderately to severely affected. In addition, edema usually occurs early when there is volume overload or illness. Serial measurements of body weight, intake and output, and serum electrolyte levels will usually provide the most precise and accurate information regarding overall fluid status. Normally, both term and preterm neonates will void within the first 24 hours after birth (Clark, 1977). In most neonates without hemodynamic compromise, urine output increases from 1–2 mL/kg per hour on the first postnatal day to 3–5 mL/kg per hour by the third to fifth postnatal day and is associated with a weight loss of 5%–10% in term infants and 10%–15% in preterm neonates (Bidiwala et al., 1988). Frequently, onset of diuresis heralds resolution of RDS (Engle et al., 1983). In critically ill newborns and in situations of altered homeostasis, additional clinical data that may help in diagnosis and management include blood urea nitrogen (BUN) levels, serum and urine osmolarity or specific gravity, and urine electrolyte and serum bicarbonate levels, along with close monitoring of blood pressure and heart rate. The frequency of monitoring depends on the extent of immaturity, the underlying pathologic condition, and the severity of the fluid and electrolyte disturbance.

Water Homeostasis and Management Water Losses

Free water loss can be categorized as either insensible (skin and respiratory track) or sensible (urine and feces). Urine output is the most important source of sensible water loss. Extremely preterm neonates without systemic hypotension or renal failure usually lose 30–40 mL of water per kilogram per day in the urine on the first postnatal day and approximately 120 mL/kg per day by the third day. In stable, more mature preterm neonates born after 28 weeks’ gestation, urinary water loss is approximately 90 mL/kg per day on the first postnatal day and 150 mL/kg per day by the third day (Coulthard and Hey, 1985). Because of their renal immaturity, preterm neonates have a tendency to produce dilute urine, thereby increasing their obligatory free water losses. In term neonates, urinary water loss is considerably less, approximating 40–60 mL/kg per day by the third day. Normal water losses in the stool are less significant, amounting to approximately 10 mL/kg per day in term neonates and 7 mL/ kg per day in preterm neonates during the first postnatal week (Sedin, 1995). Water losses in the stool increase thereafter and are influenced by the type of feeding and the frequency of stooling, which is higher in breastfed neonates. In the preterm neonate, consideration of daily insensible water losses (IWLs) through the skin is critical (see Fig. 30.4). During the first few postnatal days, in a nonhumidified environment, TEWLs may be 15-fold higher in extremely premature neonates born at 23–26 weeks’ gestation than in term neonates (Sedin, 1995). Although the skin matures rapidly after birth, even in extremely immature neonates, insensible losses are still somewhat higher at the end of the first month than in the term counterparts. Prenatal steroid exposure is associated with substantially less IWL in preterm neonates (Aszterbaum et al., 1993; Sedin, 1995; Omar et al., 1999). Appropriate management of the neonate’s immediate environment most effectively counteracts the high degree of IWL through immature skin. Among environmental factors, ambient humidity has the greatest effect on TEWL. In extremely immature neonates,

a rise in the ambient humidity in the incubator from 20%–80% decreases the TEWL by approximately 75% (Sedin, 1995). However, the use of an open radiant warmer more than doubles TEWLs (Flenady and Woodgate, 2003), and it is now standard of care to maintain extremely immature neonates in humidified incubators. Other factors that increase transepidermal IWL include phototherapy, especially when the neonate is nursed under low humidity, activity, airflow, elevated body, and environmental temperature as well as skin breakdown and skin or mucosal defects (e.g., gastroschisis, epidermolysis bullosa). IWLs from the respiratory tract depend mainly on the temperature and humidity of the inspired gas mixture and on the respiratory rate, tidal volume, and dead space ventilation. In a healthy term newborn, the water loss through the respiratory tract is approximately half the total IWL if the ambient air temperature is 32.5°C and the humidity is 50% (Sedin, 1995). However, in neonates undergoing mechanical ventilation, there will be no IWL through the respiratory tract if the ventilator gas mixture is humidified at body temperature. Extraordinary water losses are also seen in the neonate requiring intensive care. The most commonly encountered extraordinary losses occur when a nasogastric tube is placed under continuous suction (discussed in Surgical Conditions). Large losses may also occur in association with phlebotomy, chest tubes, surgical drains, ostomies, and fistulas as well as with emesis or diarrhea. Management of Water Requirements

When managing the fluid status of the neonate, the clinician must consider fluid requirement dictated by three broad categories. First, any existing deficits or surpluses must be estimated. Secondly, ongoing maintenance needs to replace usual sensible and insensible losses, and support growth must be calculated. Finally, additional needs as a result of extraordinary losses should be anticipated. Importantly, while administered together, the composition of each of these fluids is unique and must be considered individually. For example, fluids given to replace ongoing losses from a chest tube or ostomy will require a different electrolyte composition than simple maintenance fluids to maintain hydration, and these will differ again from fluids given to support growth. The neonate’s prenatal history, birth weight, gestational age, and need for mechanical ventilation and the environment in which the neonate is to be cared for should be considered when initial fluid and electrolyte needs are being determined. Frequent reevaluations are necessary. The most useful parameter for monitoring fluid balance is the weight of the baby, as rapid changes in weight will reflect changes in water balance. Serial weights can be used to estimate the IWL with use of the following formulas: IWL = Fluid Intake − Urine Output + Weight Loss or IWL = Fluid Intake − Urine Output − Weight Gain. It is reasonable to initiate fluid volume on the basis of the sum of an allowance for sensible water loss of 30–60 mL/kg per day and the estimated IWL. Fig. 30.4 shows usual IWL ranges by gestational and postnatal age. Factors previously outlined that predictably affect IWL should be considered when fluids are being prescribed. Prevention of excessive IWL rather than replacement of increased IWL is associated with fewer complications in the preterm neonate and can usually be achieved by modification of the neonate’s environment. See Table 30.1 for usual maintenance fluid administration based on birth weight. These numbers are guidelines for initial

CHAPTER 30  Fluid, Electrolyte, and Acid–Base Balance 

TABLE 30.1 

Estimated Maintenance Fluid Requirements DAILY FLUID REQUIREMENTS (mL/kg)

Birth weight (g)

Day 1

Day 2

Days 3–6

Day 7+

1500

60–80

80–120

120–160

150

management only; the approach must subsequently be individualized on the basis of laboratory values and other clinical data. It is important to remember that the TBW excess and extracellular volume expansion of preterm neonates imply that their negative water and sodium balance during the first 5–10 postnatal days (see Fig. 30.2; Shaffer and Meade, 1989) represents an appropriate adaptation to extrauterine life and should not be compensated for by increased fluid administration and sodium supplementation. If this principle is not followed, and a positive fluid balance (i.e., weight gain) is achieved during the transitional period, preterm neonates have been shown to be at higher risk of a more severe course of RDS (Shaffer and Weismann, 1992) and a higher incidence of PDA (Bell et al., 1980), congestive heart failure (Bell et al., 1980), pulmonary edema (Shaffer and Weismann, 1992), necrotizing enterocolitis (Bell et al., 1979), and BPD (Van Marter et al., 1990; Oh et al., 2005). However, most of the published studies on outcomes related to fluid balance were performed in the presurfactant era and before the widespread use of corticosteroids prenatally. Infants with ELBW and others with anticipated fluid problems should be weighed daily or twice daily. Serum sodium levels should be measured every 4–6 hours until they have stabilized, usually by 3–4 days after birth, and urine output should be recorded and reviewed every 6–8 hours. In ELBW infants, electrolyte levels should be checked by 12 hours postnatally to help guide fluid management. Once data are available, fluids should be increased if weight loss is greater than 1%–2% per day in term neonates and 2%–3% per day in preterm neonates, if urine output is inappropriately low, if urine specific gravity is rising, or if serum sodium concentration is rising. Overall, expected and appropriate weight loss during the first week postnatally is up to 10% in term neonates and up to 15% in preterm neonates. Conversely, fluids should be decreased if weight is not falling appropriately and serum sodium concentration is decreasing. The goal is to reach 140–160 mL of fluids per kilogram per day by 7–10 days to allow adequate caloric intake. Treatment of Fluid Overload

Fluid overload commonly occurs in sick neonates, often because of the use of fluid bolus administration for hypotension. The diagnosis is based on weight gain, edema, and often hyponatremia. Overhydration can sometimes be prevented by the use of blood transfusions or dopamine instead of colloid or crystalloid, if appropriate, for blood pressure support. In addition to reducing the need for volume boluses, dopamine may facilitate the process of extracellular volume contraction via its renal and hormonal effects (Seri, 1995). Once overhydration has occurred, management

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is usually effected by 10%–20% decrements of total daily fluid intake and with careful monitoring of clinical and laboratory signs to ensure maintenance of adequate intravascular volume as well as normal glucose and electrolyte status while the ECF contraction occurs. While administration of albumin followed by a diuretic (e.g., furosemide) is frequently practiced in an attempt to mobilize interstitial fluid, there is little evidence to support this practice, and it may be counterproductive because of albumin leaking into the interstitial space (Uhing, 2004). Treatment of Dehydration

Dehydration in the neonate may be suspected on the basis of history or clinical signs and confirmed by laboratory studies. One may estimate the total water deficit by using weight changes, calculating total inputs and outputs, and following serial sodium levels. Appropriate treatment requires consideration of sodium status. For additional details of fluid correction and sodium management, see the discussion in Treatment of Hypernatremia.

Sodium and Potassium Homeostasis and Management Serum sodium values should generally be kept between 135 and 145 milliequivalent (mEq)/L. Sodium chloride supplementation of 1–2 mEq/kg per day should be started in preterm and sick term neonates only after completion of the postnatal extracellular volume contraction, usually after the first few days of age or after more than 5% of birth weight has been lost (Hartnoll et al., 2001). In general, as long as the neonate’s fluid balance is stable, maintenance sodium requirements do not exceed 3–4 mEq/kg per day, and providing this amount usually ensures the positive sodium balance necessary for adequate growth. However, extreme prematurity and pathologic conditions associated with delayed transition or disturbance of fluid and electrolyte balance may significantly alter the neonate’s daily sodium requirement. For example, although preterm neonates have a limited ability to excrete a sodium load (Hartnoll, 2003), they also may waste large amounts of sodium in their urine. In addition, neonates recovering from an acute renal insult and preterm neonates with immature proximal tubule functions who are in a state of extracellular volume expansion (Ramiro-Tolentino et al., 1996) may need daily sodium bicarbonate (NaHCO3) supplementation to compensate for their greater renal bicarbonate losses. Hyponatremia

Hyponatremia (serum sodium concentration 20 mEq /L

Urine [Na] 20 mEq/L

Extrarenal losses: 1. Gastrointestinal (vomiting, diarrhea, drainage tubes, fistulas) 2. Pleural effusions, ascites 3. Ileus 4. Necrotizing enterocolitis

Renal losses: 1. Diuretics 2. Osmotic diuresis 3. Contraction alkalosis 4. Mineralocorticoid deficiency 5. Mineralocorticoid unresponsiveness 6. Fanconi syndrome 7. Bartter syndrome 8. Obstructive uropathy

1. Glucocorticoid, thyroid 2. Excess ADH

Edema-forming states: 1. Congestive heart failure 2. Liver failure/cirrhosis 3. Nephrosis syndrome 4. Indomethacin therapy

Renal failure: 1. Acute 2. Chronic

Volume expansion

Volume expansion

Water restriction

Sodium and water restriction

Sodium and water restriction

• Fig. 30.5  Flow diagram for the clinical evaluation of and therapy for neonates with hyponatremia. ADH, Antidiuretic hormone; ECF, extracellular fluid. (Modified from Avner ED. Clinical disorders of water metabolism: hyponatremia and hypernatremia. Pediatr Ann. 1995;24:23–30.)

hyponatremia in the sick neonate is excessive administration or retention of free water. In these situations the TBS content is normal, and the appropriate treatment is restriction of free water intake and not administration of sodium. In situations of true sodium deficit, one can estimate the deficits by assuming 70% of total body weight as the distribution space of sodium. The formula for calculating sodium (Na+) deficit is: Na + Deficit (or Excess) (mEq ) ≈ 0.7 × Body Weight ( kg ) × ([Na + ]desired − [Na + ]current ). In most situations of depletional hyponatremia (i.e., true sodium deficit), two-thirds of the replacement sodium should be provided in the first 24 hours, and the remainder should be provided in the next 24 hours. Frequent measurements of serum levels of electrolytes are needed to ensure that the correction is occurring appropriately. With severe hyponatremia (serum sodium concentration 150 mEq/L) reflects a deficiency of water relative to TBS and is most often a disorder of water rather than sodium homeostasis. The presence of hypernatremia does not reflect the TBS content, which can be high, normal, or low depending on the cause of the condition.

CHAPTER 30  Fluid, Electrolyte, and Acid–Base Balance 

• BOX 30.2  Conditions Causing Hypernatremia Hypovolemic Hypernatremia Inadequate breast milk intake Diarrhea Radiant warmers Excessive sweating Renal dysplasia Osmotic diuresis

Euvolemic Hypernatremia Decreased Production of Antidiuretic Hormone Central diabetes insipidus, head trauma, central nervous system tumors (craniopharyngioma), meningitis, or encephalitis

Decreased or Absence of Renal Responsiveness Nephrogenic diabetes insipidus, extreme immaturity, renal insult, and medications such as amphotericin, hydantoin, and aminoglycosides

Hypervolemic Hypernatremia Improperly mixed formula Sodium bicarbonate administration Sodium chloride administration Primary hyperaldosteronism

Hypernatremia can also be associated with hypovolemia, normovolemia, or hypervolemia (Box 30.2). If hypernatremia is primarily due to changes in sodium balance, it can result from pure sodium gain or, more commonly, sodium gain coupled with a lesser degree of water accumulation or, rarely, water loss. It is important to recognize that neonates with hypernatremic dehydration often do not demonstrate overt clinical signs of intravascular depletion and dehydration until late in the course of the condition. The hypernatremia-induced hypertonicity causes water to shift from the intracellular to the extracellular compartment, resulting in intracellular dehydration but with relative preservation of the extracellular compartment. Compared with other organs, the CNS has a unique and more effective adaptive capacity to respond to the hypernatremia-induced hypertonicity, leading to a relative preservation of neuronal cell volume. The shrinkage of the brain stimulates the uptake of electrolytes such as sodium, potassium, and chloride (immediate effect). However, these electrolytes, at higher than normal intracellular concentrations, have severe adverse effects on intracellular enzyme functions. The concomitant, hypernatremia-induced and hyperosmolality-induced synthesis of osmoprotective amino acids and organic solutes (delayed response, starting perhaps around 4–6 hours into the process) thus serves as a defensive mechanism to protect cellular functions. These idiogenic osmols, such as taurine, glycine, glutamine, sorbitol, and inositol aid in maintaining normal brain cell volume during longer periods of hyperosmolar stress and limit the accumulation of intracellular sodium and chloride (Trachtman, 1991). As long as hypernatremia develops rapidly (within hours), as in accidental sodium loading, a relatively rapid correction of the condition is usually safe. Intracellular fluid accumulation does not occur because the accumulated electrolytes (sodium, potassium, and chloride) are rapidly extruded from the brain cells, and the development of cerebral edema is unlikely. In these cases, reducing serum sodium concentration by 1 mEq/L per hour (24 mEq/L per day) is appropriate (Adrogue and Madias, 2000). In contrast to rapidly developing hypernatremia, in cases of chronic hypernatremia, the dissipation of idiogenic osmols in

377

response to correction of the hypernatremia occurs slowly over several days (Adrogue and Madias, 2000). Thus in these chronic cases, or in cases in which the time frame over which hypernatremia developed is unknown, the hypernatremia should be corrected more slowly, at a maximum rate of 0.5 mEq/L per hour (12 mEq/L per day). If correction is performed more rapidly in these cases, the abrupt fall in the extracellular tonicity results in the movement of water into the brain cells, which have a relatively fixed hypertonicity because of the presence of the osmoprotective molecules. The result is the development of brain edema with potentially deleterious consequences (Molteni, 1994; Adrogue and Madias, 2000). More recently, a large population-based study showed that neonates admitted to hospital with dehydration (weight loss >12% of birth weight) and hypernatremia (serum sodium concentration ≥150 mEq/L), but without shock, respiratory failure, infarct, or gangrene and in a managed care setting, did not have increased rates of adverse neurodevelopmental outcome at 5 years (Escobar et al., 2007). The authors noted that these favorable outcomes may not be generalizable to neonates presenting with more severe symptoms. In the breastfed term neonate, hypernatremia most commonly develops in association with dehydration secondary to inadequate breast milk intake (Molteni, 1994) but has also been associated with high sodium levels in maternal breast milk, especially from mothers of neonates not successfully lactating (Peters, 1989; AbuSalah, 2001; Karthikeyan and Modi, 2003; Scott et al., 2003). Reduction in breastfeeding frequency has been shown to be associated with a marked rise in the sodium concentration of breast milk (Neville et al., 1991). Thus the initial clinical presentation of neonates with breastfeeding-associated hypernatremia is a bodyweight loss of 10% or more, poor hydration state, lethargy, and poor feeding. Recognition may be delayed because these neonates may appear quiet and content initially, and, because of the slow development of the process, signs of extracellular volume contraction may be less prominent until the development of the full clinical presentation consisting of lethargy, irritability, hypotonia, and in some instances seizures, and cardiovascular collapse with renal failure. This presentation can be associated with serious CNS morbidity from both the hypertonicity (sagittal or other venous sinus thrombosis) and inappropriately rapid rehydration therapy (brain edema) (Lohr et al., 1989; van Amerongen et al., 2001). Although thorough follow-up studies of neonates with breastfeedingassociated severe hypernatremia are not available, observational studies suggest that up to 5% of these neonates experience brain damage (cerebral hemorrhage, edema, thrombosis or infarction) (Lavagno et al., 2016). In the extremely immature neonate, early hypernatremia most commonly occurs from excessive transepidermal free water losses. The condition usually develops rapidly, within 24–72 hours after birth. The diagnosis is based on the attendant decrease in body weight, an increase in serum sodium concentration, and the clinical signs of extracellular volume contraction. Prevention of this condition can usually be accomplished by frequent monitoring of serum electrolyte levels, appropriate adjustments of free water intake, and the early use of humidified incubators (Modi, 2004). Application of ointments reduces TEWL but is associated with increased rates of sepsis and is thus not recommended (Edwards et al., 2004). The central and nephrogenic forms of diabetes insipidus are much less common causes of hypernatremia and occur because of the lack of production of and renal responsiveness to vasopressin. Central diabetes insipidus can be congenital or can be acquired

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secondary to neurologic insult (Chaudhary et al., 2011). Hypernatremia can also develop in response to excessive sodium supplementation, mainly in the sick neonate receiving repeated volume boluses for cardiovascular support or NaHCO3 for metabolic acidosis. In these cases, clinical signs of edema, increased body weight, and the history of volume boluses help to establish the diagnosis. Treatment of Hypernatremia.  Thorough analysis of the medical history and the changes in clinical signs, laboratory findings, and body weight are necessary to determine the major etiologic factor in hypernatremia and thus the appropriate treatment. In the critically ill neonate, the cause of the serum sodium abnormality may be multifactorial, making the treatment strategy less straightforward. Although some cases of hypernatremia are a result of sodium excess with normal or high TBW, most cases in neonates are due to hypernatremic dehydration. Treatment of this condition is generally divided into two phases: the emergent phase, where the intravascular volume is restored, usually by administration of 10–20 mL of isotonic saline per kilogram, and the rehydration phase, where the sum of the remaining free water deficit and usual maintenance needs is administered evenly over at least 48 hours. The free water deficit can be calculated as follows: H2O Deficit (or Excess) (L ) ≈ 0.7 × Body Weight ( kg )  [Na + ]current (mEq/L )  × −1 .  [Na + ]desired (mEq/L )  In this formula, (0.7 × body weight) is the estimation of TBW. When dehydration is diagnosed, correction should generally occur over 24 hours, with half of the correction occurring over the first 8 hours and the remainder over the next 16 hours. Longer correction times are indicated when dehydration is accompanied by moderate (serum sodium concentration >160 mEq/L) to severe (serum sodium concentration ≥175 mEq/L) hypernatremia, particularly when it is chronic as discussed earlier. Alternatively, one can consider the amount of free water required to decrease the serum sodium concentration by a desired amount. The amount of free water required to decrease the serum sodium concentration by 1 mEq/L is 4 mL/kg with moderate hypernatremia but only 3 mL/kg when the serum sodium concentration is as high as 195 mEq/L (Molteni, 1994). Therefore the amount of free water required to decrease the serum sodium concentration by 12 mEq/L over a 24-hour period when hypernatremia is moderate (serum sodium concentration >160 mEq/L) is calculated as follows: Free Water Required = Current Weight ( kg ) × 4 mL/kg × 12 mEq/L or Free Water Required = Current Weight ( kg ) × 48 mL/kg per Day. The amount of free water required to decrease the serum sodium concentration by 12 mEq/L over a 24-hour period when hypernatremia is severe (serum sodium concentration >175 mEq/L) is calculated as follows: Free Water Required = Current Weight ( kg ) × 36 mL/kg per Day. The free water contents of the common IV fluids are listed in Table 30.2. It is important to note that sodium must be delivered with the free water replacement to avoid the hypernatremia being corrected too rapidly. In most mild to moderate hypernatremic

TABLE 30.2 

Free Water Content (as Volume Percent) of Common Intravenous Solutions at Normal and High Serum Sodium Concentrationsa SERUM SODIUM CONCENTRATION 145 mEq/L

195 mEq/L

Water (%)

Isotonic (%)

Water (%)

0

100

0

100

0.2% saline

22

78

17

83

0.45% saline

50

50

39

61

0.9% saline

100

0

79

21

86

14

68

32

Intravenous Fluid 5% dextrose in water

Lactated Ringer’s solution

Isotonic (%)

a

Isotonic saline provides 21% free water when given to a patient with a serum sodium concentration of 195 mEq/L and therefore will induce undesirable decreases in serum sodium concentration when used for volume resuscitation in the severely dehydrated hypernatremic neonate. Modified from Molteni KH. Initial management of hypernatremic dehydration in the breastfed infant. Clin Pediatr. 1994;33:731–740.

states (serum sodium concentration 150–160 mEq/L), during the rehydration phase, replacement fluids of 5% dextrose in 0.2% normal saline (31 mEq/L) or 0.45% normal saline (77 mEq/L) are appropriate. Infants with serum sodium levels greater than 165 mEq/L should initially be given 0.9% saline to avoid sudden drops in serum sodium concentration. When the serum sodium concentration is greater than 175 mEq/L, however, even normal saline will be hypotonic compared with the patient’s serum. In these instances of severe hypernatremia, an appropriate amount of 3% saline (513 mEq/L) should be added to the IV fluid so that the sodium concentration in the fluid is approximately 10–15 mEq/L less than the serum sodium level (Rand and Kolberg, 2001). The relative free water content of an IV solution for a specific patient with sodium perturbations can be calculated with the formula: Percentage of Free Water = 1 − (Intravenous Fluid Sodium Serum Sodium). Serum electrolyte levels should be monitored every 2–4 hours until the desired rate of decline in serum sodium concentration is established. At this point, the frequency of the laboratory measurements can be relaxed to every 4–6 hours until the serum sodium concentration is less than 150 mEq/L. The speed of correction of hypernatremia depends on the rate of its development. This approach provides a reasonable chance that the serum sodium concentration will gradually decrease to the normal range over 2–4 days. Except in cases of acute massive sodium overload, the goal should be to lower the serum sodium concentration at a rate no greater than 1 mEq/L per hour. A slower pace of correction of 0.5 mEq/L per hour is prudent in patients with hypernatremia of chronic or unknown duration to avoid iatrogenic CNS sequelae. While free water deficits are being corrected, the usual maintenance fluids and electrolytes must also be provided. Ongoing urine losses should be replaced volume for volume every 4–6 hours with a solution tailored to the urine’s electrolyte concentration (usually 0.225%–0.45% normal saline). Extraordinary losses caused by open wounds, tubes, drains, ostomies, emesis, and/or diarrhea

CHAPTER 30  Fluid, Electrolyte, and Acid–Base Balance 

TABLE 30.3 

Approximate Electrolyte Composition of Body Fluids (mEq/L)

Body Fluid

Sodium

Potassium

Chloride

20–80

5–20

100–150

Small intestine

100–140

5–15

90–130

Bile

120–140

5–15

80–120

Ileostomy

45–135

3–15

20–115

Diarrhea

10–90

10–80

10–110

Gastric

should always be considered in the dehydrated or hypernatremic infant and also accounted for in fluid management. The composition of this latter replacement solution depends on the electrolyte concentration of the fluid loss. The most common extraordinary loss, gastric fluid, contains significant amounts of sodium and chloride. See Table 30.3 for approximate electrolyte compositions of body fluids. Because of the association between hyponatremia and neurologic injury in hospitalized pediatric patients (Moritz and Ayus, 2003), thoughtful consideration of fluid tonicity must be considered when the replacement fluid composition is being determined in the treatment of hypernatremia. Some have advocated routine administration of isotonic (“normal” saline) fluids regardless of sodium requirement to avoid “hospital-acquired hyponatremia” caused by overadministration of free water (Moritz and Ayus, 2003; Powell, 2015). This approach is not without risk, given the overdose of sodium that occurs with administration of normal saline (Holliday et al., 2004, 2007). A more reasonable approach may be to base the appropriate fluid prescription on accurately assessed fluid deficits and ongoing requirements, with thoughtful consideration of sodium requirements of each compartment, as well as frequent monitoring of serum sodium changes (Holliday et al., 2004, 2007). Once serum sodium concentration, urine output, and renal function are normal, the patient should receive standard maintenance fluids, either intravenously or orally, depending on his or her condition. Potassium replacement (usually by addition of 20–40 mEq of potassium per liter of replacement fluid) should not begin until adequate urine output has been established. At this time, electrolyte status must still be monitored for an additional 24 hours to ensure that complete recovery has occurred. Hyperglycemia and hypocalcemia commonly accompany hypernatremia. The use of insulin to treat the hyperglycemia is not recommended, because it can increase brain idiogenic osmol content. Hypocalcemia should be corrected with appropriate calcium supplementation. Potassium Homeostasis and Management

Serum potassium concentration should be kept between 3.5 and 5 mEq/L. In the early postnatal period, neonates, especially immature preterm neonates, have higher serum potassium concentrations than older persons. The cause of the relative hyperkalemia of the newborn is multifactorial and involves developmentally regulated differences in renal function, sodium potassium–adenosine triphosphatase activity (Vasarhelyi et al., 2000), and hormonal milieu. Exposure to steroids prenatally in premature neonates is associated with a decreased incidence of hyperkalemia, believed to be due to improved renal function (Omar et al., 2000). In general, potassium supplementation should be started only after urine output has been well established, usually by the third

379

postnatal day. Supplementation should be started at 1–2 mEq/kg per day and increased over 1–2 days to the usual maintenance requirement of 2–3 mEq/kg per day. Some preterm neonates may need more potassium supplementation after the completion of their postnatal volume contraction because of their increased plasma aldosterone concentrations, prostaglandin excretion, and disproportionately high urine flow rates. Most neonates will require additional potassium supplementation if they are receiving diuretics. Hypokalemia.  Hypokalemia in the neonate is usually defined as a serum potassium level of less than 3.5 mEq/L. Hypokalemia can occur from potassium loss due to diuretics, diarrhea, renal dysfunction, or nasogastric drainage from inadequate potassium intake or from shift of potassium into the intracellular compartment in the presence of alkalosis. Electrocardiogram (ECG) manifestations of hypokalemia include flattened T waves, prolongation of the QT interval, or the appearance of U waves. Except in patients receiving digoxin, hypokalemia is rarely symptomatic until the serum potassium concentration is less than 2.5 mEq/L. This degree of hypokalemia can result in cardiac arrhythmias, ileus, and lethargy. Treatment of Hypokalemia.  Hypokalemia is treated by slow replacement of potassium either intravenously or orally, usually in the daily fluids. Rapid administration of potassium chloride is not recommended because it may be associated with life-threatening cardiac dysfunction. In extreme emergencies, potassium can be given as an infusion over 30–60 minutes of not more than 0.3 mEq of potassium chloride per kilogram. If hypokalemia is secondary to alkalosis, the total body potassium content is usually normal, and the alkalosis should be corrected before an increase in the potassium intake is considered. Hyperkalemia.  Hyperkalemia in the neonate is defined as a serum potassium level greater than 6 mEq/L in a nonhemolyzed specimen. It is important to understand that most of the body’s potassium is contained within cells; therefore serum potassium levels do not accurately reflect total body stores. However, a serum potassium level greater than 6.5 to 7 mEq/L can be life threatening, even if total body stores are normal or low, because of its effect on cardiac rhythm. ECG manifestations of hyperkalemia include peaked T waves (the earliest sign), a widened QRS configuration, bradycardia, tachycardia, supraventricular tachycardia, ventricular tachycardia, and ventricular fibrillation. Because pH affects the distribution of potassium between the intracellular and the extracellular space, serum potassium levels may rise acutely during acidosis. The clinician should be aware of the potential for life-threatening arrhythmias to occur in infants with chronic lung disease receiving diuretics and potassium supplements who develop a sudden respiratory deterioration with acidosis. Hyperkalemia is very common in the very preterm neonate, occurring in more than 50% of neonates weighing less than 1000 g (Mildenberger and Versmold, 2002). Another common cause of hyperkalemia is renal dysfunction, of particular concern in very preterm neonates and in neonates whose course is complicated by asphyxia or hypotension. In addition, hyperkalemia secondary to release of potassium from dying cells often complicates IVH, tissue ischemia (i.e., volvulus or necrotizing enterocolitis), and intravascular hemolysis. Less commonly, hyperkalemia may be one of the earliest manifestations of congenital adrenal hyperplasia or may occur because of other causes of neonatal acute adrenal insufficiency. Treatment of Hyperkalemia.  When hyperkalemia is diagnosed, all potassium intake should be discontinued, and the ECG should

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PART V I I I  High-Risk Newborn Care

TABLE 30.4 

Medications Used for Treatment of Hyperkalemia

Medication

Dosage

Onset

Length of Effects

Mechanism of Action

Comments and Cautions

Calcium gluconate

100 mg/kg intravenously over 2–5 min

Immediate

30 min

Protects the myocardium from toxic effects of potassium; no effect on total body potassium

Can worsen digoxin toxicity

Sodium bicarbonate

1–2 mEq/kg

Immediate

Variable

Shifts potassium intracellularly; no effect on total body potassium

Maximum infusion: mEq/min in emergency situations

Tromethamine

3–5 mL/kg

Immediate

Variable

Shifts potassium intracellularly; no effect on total body potassium

—

Insulin plus dextrose

Insulin 0.1–0.15 U/kg intravenously plus dextrose 0.5 g/kg intravenously

15–30 min

2–6 h

Shifts potassium intracellularly; no effect on total body potassium

Monitor for hypoglycemia

Albuterola

0.15 mg/kg every 20 min for three doses then 0.15–0.3 mg/kg

15–30 min

2–3 h

Shifts potassium intracellularly; no effect on total body potassium

Minimum dose 2.5 mg

Furosemide

Per os: 1–4 mg/kg per dose 15 min to 1 h once or twice per day Intravenously: 1–2 mg/kg per dose given every 12–24 h

4 h

Increases renal excretion of potassium

—

Sodium polystyrene

1 g/kg rectally every 6 h

4–6 h

Removes potassium from the gut in exchange for sodium

Use with extreme caution in neonates, especially preterm neonates; contains sorbitol; may be associated with bowel necrosis and sodium retention

1–2 h (rectal route faster)

a

From Singh BS, Sadiq HF, Noguchi A, Keenan WJ. Efficacy of albuterol inhalation in treatment of hyperkalemia in premature neonates. J Pediatr. 2002;141:16–20.

be monitored. Table 30.4 presents medications used in management of significant hyperkalemia. Calcium gluconate stabilizes cardiac membranes, and alkali therapy (sodium bicarbonate), insulin/ glucose, and inhaled albuterol (Singh et al., 2002) all rapidly enhance cellular uptake of potassium and can cause a sharp drop in serum potassium levels in life-threatening situations but will not decrease total body potassium content. Intravenously administered furosemide and rectally administered sodium polystyrene sulfonate (Kayexalate) enhance potassium excretion and will lower total body stores but require at least several hours to take effect. Furthermore, use of polystyrene sulfonate to treat hyperkalemia in preterm neonates (20 to 23 kg, 0.8 mg orally once a day for weight >23 to 26 kg, 0.9 mg orally once a day for weight >26 to 30 kg, and 1 mg orally once a day for weight >30 kg.

Chronic hepatitis B. Adjust dose for renal insufficiency

CHAPTER 37  Viral Infections of the Fetus and Newborn 

TABLE 37.2 

489

Antiviral Agents Commonly Used in Neonatology Practice—cont’d

Antiviral Agent

Indication

Dose, Route of Administration, Duration of Therapy

Comments

Interferon alfa-2b

Hepatitis B, hepatitis C

3 million to 6 million international units per square meter three times per week; up to 24 months’ duration; combined with oral ribavirin therapy for hepatitis C

Chronic hepatitis B; no data in neonates; chronic hepatitis C when administered with ribavirin; systemic side effects (fever, flulike symptoms, anorexia); leukopenia; thyroid autoantibodies

Pegylated interferon alfa-2b

Hepatitis B, hepatitis C

1.5 µg/kg once per week; no information on dosing in children aged 1.0–2.0

>2.0–6.0

SP-B/phospholipid (%)

• Fig. 48.4  Surfactant Dysfunction in Ventilated Preterm Infants. (A) Prevalence of surfactant dysfunction (minimum surface tension [STmin] >5 mN/m) during weeks 2 to 11 of life in ventilated preterm infants. (B and C) Inverse relationship of surfactant protein B (Sp-B) content (normalized to phospholipid content) to STmin in ventilated preterm infants; low surface tension is associated with higher SP-B content. STmin, Minimum surface tension; SP-B, surfactant protein B. (Adapted from Merrill JD, Ballard RA, Cnaan A, et al. Dysfunction of pulmonary surfactant in chronically ventilated premature infants. Pediatr Res. 2004;56:918–926.)

randomized studies of SP-B (or an analogue)–containing surfactants in preterm infants persistently ventilated at 3 to 14 days have also demonstrated transient decreases in ventilator support compared with controls but no effect on the prevention of BPD or death at 36 weeks (lucinactant, Discovery Laboratories, Inc., Warrington, PA; calfactant, Ony Inc., Amherst, NY; poractant alfa, Chiesi USA, Inc., Cary, NC) (Laughon et al., 2009b; Keller et al., 2012; Hascoët et al., 2016). The large multicenter Trial of Late Surfactant (TOLSURF) randomized extremely low GA newborns who remained intubated at 7 to 14 days to calfactant (up to 5 doses) in combination with iNO versus iNO alone. Although there was no effect on survival without BPD at 36 weeks’ PMA, there was a trend toward an increase in this outcome assessed at 40 weeks’ PMA, and late surfactant administration was safe and well-tolerated (Ballard et al., 2016).

Adrenal Insufficiency Preterm infants may have developmental immaturity of the hypothalamic–pituitary–adrenal axis, with an increased risk of BPD secondary to inadequate responses to inflammatory lung injury (Watterberg and Scott, 1995; Watterberg et al., 1996). Banks

et al. reported, however, in a study of cortisol levels in 314 preterm infants, that even the earliest gestation infants (24–25 weeks) have an increase in cortisol after delivery and that levels were not associated with GA (Fig. 48.5) (Banks et al., 2001). Using the Clinical Risk Index for Babies score to adjust for clinical risk factors, low cortisol at 3 to 7 days of age contributed minimally to increasing the risk for BPD, and there was no correlation at 14 to 28 days. A subsequent cohort of infants from the PROPHET (Prophylaxis of Early Adrenal Insufficiency to Prevent Bronchopulmonary Dysplasia) study demonstrated no relationship between cortisol levels in the first week and BPD, although higher cortisol levels were associated with increasing incidence of other acute and chronic morbidities (Aucott et al., 2008, 2010). Three randomized studies, including PROPHET, investigated “physiologic replacement” hydrocortisone dosing (total dose of 8.5–13.5 mg/kg over 10–15 days) for the prevention of BPD in extremely preterm newborns (Watterberg et al., 2004; Peltoniemi et al., 2005; Baud et al., 2016). Two of the studies were terminated prematurely due to increased rates of intestinal perforation in the hydrocortisone-treated group. No benefit on the primary outcome of survival without BPD in either study was seen (Watterberg et al., 2004; Peltoniemi et al., 2005).

CHAPTER 48  Bronchopulmonary Dysplasia

25

24–25 weeks (n = 81) 26–27 weeks (n = 98) 28–32 weeks (n = 135)

Cortisol (µg/dL)

20 15 10 5

687

• BOX 48.2 Nonpharmacologic and Pharmacologic

Approaches to Preventing Bronchopulmonary Dysplasia

Nonpharmacologic Approaches Ventilation strategies: maintenance of FRC/low-volume ventilation/optimize nasal continuous distending airway pressure/gentle ventilation Strict fluid balance Early enteral nutrition Early protein administration

Pharmacologic Approaches

0 cord

2h

1 day

3–7 days 14–28 days

• Fig. 48.5

  Plasma Cortisol Concentrations in Premature Infants During the First 4 Weeks of Life. Data are mean levels stratified by gestational age: 24–25 weeks (n = 81), 26–27 weeks (n = 98), and 28–32 weeks (n = 135).

The most recent study differed, as the cumulative hydrocortisone dose was lower than in the other studies, and it enrolled only inborn infants, with no requirement for mechanical ventilation (Baud et al., 2016). Other differences included limitations on use of ibuprofen and open-label glucocorticoids. This study did show a benefit of increased survival without BPD (odds ratio 1.48, 95% CI 1.02–2.16), with fewer infants intubated on mechanical ventilation at 7 days and with no increase in adverse events in the intervention group. Although the PROPHET study demonstrated a significant interaction between clinical chorioamnionitis and hydrocortisone treatment (with the infants exposed to the antiinflammatory steroid more likely to survive without BPD), other studies have not demonstrated this differential effect. Of interest is the fact that formation of alveolar septae in animals, a critical step in alveologenesis, occurs during a period of low serum glucocorticoid levels. Furthermore, dexamethasone administered to newborn rodents results in persistent impaired septation and alveologenesis (Massaro and Massaro, 2000). Thus there is not consistent evidence that adrenal insufficiency contributes to BPD in the general population of at-risk premature infants.

Inhibition of Normal Lung Development and Vascular Development Some of the contributing factors described above directly impair normal formation of secondary septae and therefore microvascular development and alveolarization. Others arrest alveolarization by as-yet unknown processes that also involve structural differences in the extracellular matrix. These insults, occurring during the saccular stage of lung development, include inflammation and cytokine overexpression, dexamethasone exposure, hyperoxia, hypoxia, and inadequate nutrition (Albertine et al., 1999; Jobe, 1999; Massaro and Massaro, 2000; Massaro et al., 2004). Fig. 48.6 shows imaging and pathology from an infant who died from BPD complicated by pulmonary hypertension.

Preventive Factors The Bronchopulmonary Dysplasia Group, convened to identify strategies for investigation of therapies to prevent or treat BPD, proposed classes of drugs to prevent or treat evolving (at 7 to 14 days) BPD (Walsh et al., 2006). These included antiinflammatory

Vitamin A Postnatal steroids: systemic, inhaled, instilled Inhaled nitric oxide Caffeine FRC, functional residual capacity.

agents such as prenatal and postnatal corticosteroids (PNCS) and other small molecules, antioxidants, iNO, late surfactant replacement, and improved vitamin A preparations. Additional approaches that have been proposed and evaluated include alternative ventilation strategies and the primary use of nasal CPAP. Box 48.2 lists both nonpharmacologic and pharmacologic approaches to preventing or decreasing severity of BPD, with these approaches and others discussed further in this section.

Prenatal Steroids Numerous clinical studies and several large metaanalyses have demonstrated that prenatal glucocorticoids administered to women at high risk for premature delivery result in decreased mortality and morbidity associated with prematurity, including RDS, intraventricular hemorrhage, and necrotizing enterocolitis (NEC) (Roberts and Dalziel, 2006). However, the benefit of prenatal glucocorticoids for prevention of BPD among survivors is not consistent. The nonsignificant effect of prenatal steroids on BPD may be due to the increased survival of higher risk, less mature preterm infants following prenatal glucocorticoid exposure.

Surfactant Replacement Therapy Surfactant replacement therapy is clearly associated with decreased severity of RDS and its associated mortality. Although survivors do not have a decreased incidence of BPD, a decrease in BPD or death was demonstrated in a recent metaanalyses (Seger and Soll, 2009). Investigations of late surfactant replacement, during a period of secondary surfactant dysfunction (Merrill et al., 2004), for prevention of BPD in those infants that continue to require mechanical ventilation after the first week of life, have been undertaken. Several pilot randomized studies and one larger trial evaluated the effects of late surfactant replacement on the respiratory status of extremely preterm infants requiring mechanical ventilation from days 3 to 14 (Laughon et al., 2009b; Keller et al., 2012; Ballard et al., 2016; Hascoët et al., 2016). In addition to improved surfactant function and increased levels of SP-B following late surfactant replacement in these infants at high risk for surfactant dysfunction, these exogenous surfactant preparations (calfactant, poractant alfa) have antioxidant activity, which may mitigate the

688

PART X  Respiratory System

A

B

C

D

• Fig. 48.6  Pulmonary Imaging and Pathology in a Former Preterm Infant With a History of Oligohydramnios, With Severe Bronchopulmonary Dysplasia and Pulmonary Hypertension at 44 Weeks’ Postmenstrual Age. (A) Computed tomography scan with contrast demonstrating patchy consolidation and mosaic perfusion, consistent with poor ventilation–perfusion matching. (B) Postmortem pathology demonstrates alveolar enlargement, consistent with alveolar simplification. (C) On higher magnification, pulmonary vascular changes indicative of pulmonary hypertension are present. (D) Patchy septal thickening is seen on higher magnification.

effects of ongoing lung inflammation and oxidative stress for these persistently intubated infants (Dani et al., 2009; Merrill et al., 2011; Keller et al., 2012). Despite transient (up to 24 hours) decreases in level of respiratory support, late surfactant failed to significantly increase survival without BPD at 36 weeks’ PMA in all of these studies (Laughon et al., 2009b; Keller et al., 2012; Ballard et al., 2016; Hascoët et al., 2016). However, the two studies that evaluated later outcomes (at 9–12 months corrected age) suggested that late surfactant decreased respiratory resource utilization following neonatal hospital discharge (Hascoët et al., 2016; Keller et al., 2016b).

Gentle Ventilation and Nasal Continuous Positive Airway Pressure As described previously, volutrauma as well as atelectasis contributes directly to lung damage and the release of cytokines, which further the cycle of damage. With respect to respiratory support strategies for extremely preterm newborns, the body of evidence suggests that a primary strategy of nasal continuous distending airway pressure (as CPAP, biphasic CPAP, or intermittent positive pressure ventilation), expeditious transition to nasal continuous distending airway pressure for those infants who require early surfactant

CHAPTER 48  Bronchopulmonary Dysplasia

replacement therapy, and patient-triggered low-volume ventilation for those infants who are unable to be extubated are safe approaches to respiratory support that may decrease the incidence of BPD. These studies have been done under stringent protocols for respiratory management based on clinical status, level of respiratory support, and blood gas parameters, which is probably important for both potential risks and benefit of these approaches. Regardless, the current evidence does not support a primary strategy of highfrequency ventilation or the use of high-flow nasal cannula in lieu of nasal CPAP in extremely premature infants. Furthermore, there is no evidence to support a target oxygen saturation of 85%–89% (vs 91%–95%) to decrease supplemental oxygen exposure from birth for prevention of BPD—mortality may be increased in subgroups of preterm newborns, while rates of BPD are not significantly decreased. However, there are not currently adequate data to otherwise identify an appropriate oxygen saturation target; higher oxygen saturation targets are associated with increased rates of severe retinopathy of prematurity, and in addition to mortality, rates of NEC may be increased with lower oxygen saturation targets (Manja et al., 2015).

Vitamin A Vitamin A is an essential nutrient for maintaining respiratory tract epithelial cells and also is stored in the septal cells of the alveoli involved in alveolar septation. Compelling animal data also support the need for vitamin A (see Fig. 48.6) (Albertine et al., 1999). Because vitamin A is accumulated predominantly in the third trimester, preterm infants have deficient liver stores of this vitamin (Zachman, 1989). These infants, who often are unable to tolerate enteral feedings, are at particular risk for vitamin A deficiency since vitamin A added to parenteral nutrition solutions is degraded by light and can adhere to the intravenous tubing, making it largely inaccessible. A number of clinical trials have investigated whether supplementation with vitamin A, typically by intramuscular injections, would result in a decrease in BPD. The largest study to date, by the NICHD-funded NRN, also used one of the higher doses that has been studied and demonstrated a decrease in BPD or death at 36 weeks following treatment with vitamin A (55% vs 62%) (Tyson et al., 1999). A recent metaanalysis of all published trials revealed that vitamin A supplementation was associated with a modest reduction in death or BPD at 36 weeks, which was of borderline statistical—and perhaps clinical—significance (RR 0.91, 95% CI 0.82–1.00, number needed to treat [NNT] 17) (Darlow and Graham, 2011). Vitamin A is well tolerated, and there are no safety issues, although it does involve repeated intramuscular injections. A recent report found that costs associated with intramuscular vitamin A administration for prevention of BPD were favorable if multiple infants were being treated concurrently with doses drawn from the same vial but substantially higher when vials were used for single dose administration (Couroucli et al., 2016). Interestingly, survey data have shown that a minority of centers routinely administer vitamin A supplementation to at-risk infants, with inadequate evidence or lack of substantial effect cited as the rationale for lack of supplementation (Ambalavanan et al., 2004). Furthermore, data analyzed from before and during a period of a national shortage of the vitamin A preparation (2010–2012) demonstrated a large fall in vitamin A administration in at-risk infants from greater than 30% to less than 5% of the target population (Tolia et al., 2014). However, there was no change in the rate

689

of death of BPD for these at-risk infants over these two epochs, data which were further supported in multivariate analysis controlling for other risk factors for BPD. Thus the efficacy of vitamin A for prevention of BPD may be lacking in the setting of contemporary strategies for the care of the extremely preterm newborn (Gawronski and Gawronski, 2016).

Systemic Postnatal Corticosteroids Preterm infants given PNCS demonstrate some decreased inflammatory markers and suppression of cytokine-mediated inflammatory reactions in their tracheal aspirates. Other than direct antiinflammatory effects, numerous theoretical reasons have been advanced regarding why postnatal administration of steroids might decrease the incidence of BPD, including the potential for increased surfactant synthesis, enhanced β-adrenergic activity, increased antioxidant production, stabilization of cell and lysosomal membranes, and inhibition of prostaglandin and leukotriene synthesis (Watterberg et al., 1999). These potential benefits are balanced against the knowledge that dexamethasone exposure results in persistent decreases in alveolar numbers in animal models and irreversible effects on brain development (Massaro and Massaro, 2000; Kreider et al., 2006; Heine and Rowitch, 2009; Bhatt et al., 2013). Clinical trials have demonstrated acute improvements in dynamic compliance and pulmonary resistance following treatment with PNCS, although small follow-up studies have demonstrated no differences in reported respiratory morbidity despite a trend toward improved pulmonary function in children greater than 5 years of age treated with dexamethasone (Nixon et al., 2007; Doyle et al., 2014b). Many have separated out the effects of early (≤7 days) versus late (>7 days) initiation of PNCS predominantly because of differences in adverse side-effect profiles based on the timing of exposure. Based on two recent metaanalyses (Doyle et al., 2014a, 2014b), postnatal dexamethasone has similar beneficial effects on death or BPD at 36 weeks (RR 0.76–0.89, 95% CI, 0.68–0.94), decreased need for mechanical ventilation at 3 to 28 weeks after initiation of therapy, and no significant effect on survival to hospital discharge regardless of the timing of drug initiation. Aggregated studies of hydrocortisone administered in the first week of life demonstrate no effects on mortality or BPD, although this analysis was prior to the results of the most recent trial (Baud et al., 2016). Major concerns exist regarding both short-term and long-term side effects of PNCS, including systemic hypertension, hyperglycemia and glycosuria, hypertrophic cardiomyopathy, adrenal suppression, and decreased growth. Early administration of PNCS in the first week after birth carries an increased risk of gastrointestinal perforation for both dexamethasone and hydrocortisone (RR 1.81, 95% CI 1.33–2.48) (Doyle et al., 2014a). This effect may be associated with concurrent administration of indomethacin (Watterberg et al., 2004). Gastrointestinal hemorrhage is also significantly increased (RR 1.87, 95% CI 1.35–2.58) with early dexamethasone. Individual studies have reported an increased risk of later cerebral palsy (CP) in children treated early with dexamethasone (Yeh et al., 1998; Shinwell et al., 2000). The metaanalyses support this concern for dexamethasone (with no effect seen with hydrocortisone); the relationship was not statistically significant when treatment is initiated after 7 days of age (Doyle et al., 2014a, 2014b). In recognition of these accumulated findings, a statement from the American Academy of Pediatrics revised a previous recommendation against any routine use of postnatal dexamethasone in preterm infants (Watterberg et al., 2010). The current statement

690 PART X  Respiratory System

distinguishes between high-dose dexamethasone administration, which is not recommended, and low-dose dexamethasone administration, where current evidence of benefit versus risk is lacking. Additional recent assessments illustrate overlap between the NNT (prevent BPD) and the number needed to harm (abnormal neurologic outcome, including CP) for early dexamethasone treatment, which may be related both to the cumulative dose of the medication and an individual infant’s risk for BPD (Schmidt et al., 2008; Onland et al., 2009; Doyle et al., 2014c; Jensen et al., 2015). A large cohort study demonstrated a dose-dependent increased risk of death or neurodevelopmental impairment (NDI) at 18 to 22 months corrected age, regardless of PMA at the time of dexamethasone exposure (Wilson-Costello et al., 2009). However, the excess risk caused by PNCS exposure was decreased for those infants at highest risk for BPD. Similarly, in a metaregression of randomized trials, Doyle et al. (2014c) demonstrated that the excess risk of CP caused by dexamethasone exposure was obliterated with increasing rates of BPD in the control group. Essentially, at an underlying BPD incidence of 46% (95% CI 33%–60%), there was no excess risk of the outcome of CP or death and a diminishing risk with higher rates of BPD. With respect to dose, a separate metaregression analysis suggested that higher cumulative dexamethasone dose was inversely associated with rates of BPD, for infants with treatment initiated in the first 2 weeks of life (Onland et al., 2009). With respect to NDI, earlier treatment initiation had an inverse relationship to risk of NDI. However, for later treatment, the relationship was reversed, with higher doses associated with higher risk of NDI, although this relationship was not significant. The interpretation of the cumulative data therefore is challenging, as infants who are studied outside of a randomized trial may not have appropriate controls, because of the bias regarding who is treated clinically, whereas open-label use of PNCS during clinical trials alters the ability to assess both beneficial and adverse effects of treatment (Onland et al., 2010). An ongoing study aims to address the issue of safety and efficacy of later treatment with hydrocortisone (The Hydrocortisone for BPD study, NCT01353313). In this study, extremely preterm newborns who continue to require mechanical ventilation at 14 to 28 days are randomized to hydrocortisone or placebo. In addition to the later timing of intervention, this study protocol entails a higher dose of hydrocortisone than had been previously administered in randomized trials (18 mg/kg over 10 days). Follow-up of growth and development at 22 to 26 months corrected age is also being undertaken, to fully understand both benefits and risks of this intervention. However, it is also possible that this window of intervention will be too late to “prevent” BPD, as the underpinnings of the disorder may already be established. For instance, in the NO CLD study, infants treated with iNO initiated at 7 to 14 days had decreased BPD rates, whereas those with the drug initiated at 15 to 21 days had no effect (Ballard et al., 2006; Ballard, 2007). A recent secondary analysis from TOLSURF of cumulative supplemental oxygen exposure over the first 28 days also demonstrated that there was no additional predictive value for this index beyond 14 days (Wai et al., 2016). Overall, the data suggest that the subset of infants at highest risk for BPD may benefit from dexamethasone. Although the optimal timing of this intervention is not clear, it seems prudent to avoid the concurrent administration of PNCS and inhibitors of prostaglandin synthesis (e.g., indomethacin, ibuprofen) early in the postnatal course. Regardless, there are insufficient data to support the use of any other systemic steroid at this point in time.

Inhaled/Instilled Corticosteroids Because of concern for systemic effects of PNCS, there has been continued interest in local delivery of steroids to the lung. Although inhaled steroids initiated in the first 2 weeks have been studied for prevention of BPD, there were not significant improvements in either immediate or later respiratory status with this intervention, including no significant effect on death or BPD in a metaanalysis (Shah et al., 2012). There was a trend toward decreased systemic PNCS use in these infants and no increase in rates of the acute side effects seen with systemic PNCS administration (compared to placebo). A recent study of inhaled budesonide (delivered by metered-dose inhaler with spacer) in extremely low GA newborns receiving positive pressure in the first day after birth had a borderline significant effect on death or BPD (RR 0.86, 95% CI 0.75–1.00) (Bassler et al., 2015). Infants were treated until 32 weeks’ PMA or off positive pressure support (whichever came first) with an average of 33.9 ± 15.9 days for infants in the budesonide group. Although BPD was decreased in survivors in the budesonide-treated group, mortality was nonsignificantly increased. There were fewer infants reintubated in the intervention group, fewer undergoing PDA ligation, and no increase in rates of potential side effects or growth parameters over the first 28 days. These data are interesting with respect to the pulmonary effects, but the higher mortality in the treated group raises concerns for systemic absorption of budesonide, as the target tissue for inhaled drugs is the airway, but proximal deposition of drug also occurs. Instillation of budesonide by suspending it in surfactant provides another method of budesonide delivery to the lung, which may more selectively reach the lung parenchyma. In fetal lung explants, incubation with budesonide suppresses inflammatory markers by 90% 12 hours after addition of budesonide (Barrette et al., 2016). This effect was unchanged after budesonide was suspended in calfactant, and surface tension of calfactant was minimally affected. Budesonide suspended in calfactant administered intratracheally to preterm lambs demonstrates a plasma half-life of 4.76 ± 1.79 hours, with nonmetabolized budesonide and budesonide palmitate (fatty acid ester), but not the primary metabolite of budesonide, present in lung tissue (Roberts et al., 2016). Neither budesonide nor its metabolites were found in brain tissue, suggesting that the budesonide absorbed systemically did not cross the blood–brain barrier. A pilot study of budesonide (0.25 mg/kg) with Survanta (beractant, Abbott Laboratories, Columbus, OH) compared to Survanta alone for treatment of RDS in very low birth weight preterm infants similarly demonstrated a plasma half-life of 4.13 hours with only approximately 4% of the budesonide dose calculated to enter the systemic circulation, based on drug and metabolite levels (Yeh et al., 2008). In this study, respiratory status improved over 1 to 3 days, and treated infants were extubated earlier, compared with infants treated with beractant alone, without an increase in acute adverse effects. There was also a significantly lower rate of death or BPD. A larger multicenter study extended these findings, demonstrating decreased death or BPD (RR 0.58, 95% CI 0.44–0.77), with both lower mortality and BPD rates in the budesonide-treated group and no increase in comorbidities of prematurity (Yeh et al., 2016). Furthermore, tracheal aspirate inflammatory markers were lower in treated infants than controls: IL-1 and IL-6 were decreased at 12 hours after the intervention, and IL-8 was decreased for up to 8 days following the intervention. Neurodevelopmental follow-up from these trials did not suggest an increase in NDI at 2 to 3 years corrected age, although these studies were underpowered to detect significant differences (Kuo

CHAPTER 48  Bronchopulmonary Dysplasia

Antioxidant Therapy Some evidence in the baboon model of BPD indicates that a catalytic antioxidant, metalloporphyrin, can protect against hyperoxiainduced lung injury (Chang et al., 2003). Superoxide dismutase is a naturally occurring enzyme that protects against oxygen free radical injury. Human studies have suggested that administration of intratracheal rhSOD is well-tolerated and might have beneficial effects on the lung; a randomized trial of rhSOD, which was stopped prematurely because of lack of efficacy for prevention of BPD, demonstrated an improvement in respiratory morbidity at 1 year corrected age (Davis et al., 2003). Other therapies proposed to prevent BPD may provide or augment antioxidant activity (e.g., mesenchymal stem cell transplant, exogenous surfactant replacement), which is one potential mechanism by which they might have an effect on the development of BPD.

Inhaled Nitric Oxide Prolonged iNO from birth in animal models of BPD improves endogenous surfactant function as well as lung growth, angiogenesis, and alveogenesis (Bland et al., 2005; McCurnin et al., 2005). In addition, recovery from injury using iNO attenuates the impaired alveolar and microvascular development associated with prolonged hyperoxia exposure in the rodent (Lin et al., 2005). Prematurity in the baboon, and presumably in the human, is associated with developmentally deficient endogenous nitric oxide production (Shaul et al., 2002). Accordingly, iNO following preterm birth may be viewed as replacement therapy. Multiple studies of iNO initiated in the first 72 hours after birth, for prevention of BPD in ventilated preterm infants, have been conducted—with results showing variable efficacy (Kinsella et al., 1999, 2006; Schreiber et al., 2003; Van Meurs et al., 2005; Mercier et al., 2010). Safety concerns were raised in the single study that enrolled sicker infants with a higher baseline oxygenation index, because of increased severe intracranial hemorrhage (Van Meurs et al., 2005), but improved neurologic outcomes were found in less ill newborns (Mestan et al., 2005; Kinsella et al., 2006). These studies treated infants for variable duration, up to 21 days, with doses of 5–10 ppm. Kinsella et al. (2014) also studied preterm infants who were not intubated, but required respiratory support in the first 3 days, and found no benefit of iNO for prevention of BPD. In the NO CLD Trial, which enrolled ventilated infants 500 to 1250 grams at 7 to 21 days who had evolving BPD, infants received at least 24 days of iNO therapy, with a dose of 10–20 ppm for at least 10 days (Ballard et al., 2006; Ballard, 2007) (Fig. 48.7 shows a comparison of dosing and duration of trials). In this study, the rate of survival without BPD at 36 weeks significantly increased from 37% to 44%, and fewer days of ventilation resulted in a relative cost savings with iNO (Zupancic et al., 2009). There was a significant interaction of treatment with the age at study entry, with infants that entered earlier (at 7–14 days) being more likely to benefit (increase in survival without BPD from 27% to 49% (NNT = 4). The benefit of treatment persisted at 40 weeks’ PMA, with iNO-treated infants more likely to be discharged or hospitalized

Ballard (180) Kinsella (~70) Schreiber (~40) Van Meurs (~15)

20

15 iNO (ppm)

et al., 2010; Yeh et al., 2016). Thus instilled budesonide may achieve local glucocorticoid (including antiinflammatory) effects on the lung, without adverse systemic and neurodevelopmental consequences. However, the appropriate dose and target population for a definitive study to prevent BPD remain to be determined, as the dose administered by Yeh et al. was substantial.

691

Mercier (~100)

10

5

0 0

5

10

15

20 25 Days of life

30

35

40

• Fig. 48.7

  Summary of Large Trials of Inhaled Nitric Oxide for Prevention of Bronchopulmonary Dysplasia by Day of Life Versus Inhaled Nitric Oxide Dose. Duration of treatment and total nitric oxide dose are depicted. iNO, Inhaled nitric oxide; ppm, parts per million. (Adapted from Truog WE. Inhaled nitric oxide for the prevention of bronchopulmonary dysplasia. Expert Opin Pharmacother. 2007;8:1505–1513.)

without respiratory support, and both the earlier and later (15–21 days) treated groups had evidence of benefit at that point in time (Keller et al., 2009). Furthermore, pulmonary morbidity at 1 year was decreased in the iNO-treated group (fewer infants requiring supplemental oxygen and decreased use of bronchodilators, diuretics, and inhaled and systemic steroids). All subgroups of treated infants benefited (Hibbs et al., 2008). iNO therapy initiated at 7 to 21 days was also safe. There was no difference in the rate of comorbidities of prematurity between the treatment and control groups and no difference in the rate of neurodevelopmental impairment by treatment group at 2 years corrected age (Walsh et al., 2010). A systematic review of studies in ventilated infants demonstrated an overall modest benefit of iNO that was not statistically significant (RR 0.90–0.94, 95% CI 0.80–1.02) (Barrington and Finer, 2010). However, an individual-patient data (IPD) metaanalysis did demonstrate a modification of the iNO effect by initial iNO dose: trials with a starting dose greater than 5 ppm demonstrated significant benefit (RR 0.83, 95% CI 0.74–0.95), a response which was not seen in trials with a starting dose greater than 5 ppm (P = .02 for interaction) (Askie et al., 2011). A more recent IPV, including newer data from an as-yet unpublished study conducted by the company that manufactures iNO (INOmax, Mallinckrodt Inc., St. Louis, MO) demonstrated that, in studies of ventilated infants with iNO starting dose of greater than 5 ppm, infants of black mothers were more likely to respond to iNO than other infants (P = .01 for interaction) (Ballard et al., 2016). Another potential predictor of iNO response is low endogenous nitric oxide production before therapy. The lowest quartile of nitric oxide metabolites in tracheal aspirate fluid at study entry was associated with the highest rate of survival without BPD in the NO CLD study (Posencheg et al., 2010). Thus it may be that there are subpopulations of infants that are more likely to respond to iNO, when given at an effective dose.

Caffeine Schmidt et al. reported that the administration of caffeine, initiated in the first 10 days to facilitate extubation, or to prevent or treat apnea of prematurity, decreased the risk of BPD at 36 weeks from

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PART X  Respiratory System

47% to 36% in infants 500–1250 grams in the Caffeine for Apnea of Prematurity (CAP) Trial (Schmidt et al., 2006). Infants treated with caffeine were permanently weaned off mechanical ventilation, positive airway pressure, and supplemental oxygen approximately 1 week earlier, with less exposure to PNCS and lower rates of treatment for PDA. Caffeine was discontinued at a median of 34 weeks’ PMA. There was a transient decrease in weight gain in treated infants, but no other substantial adverse effects were seen. A post hoc analysis of subgroups of infants demonstrated similar effects of caffeine on prevention of BPD, regardless of the indication for initiation of therapy and whether infants were on noninvasive or invasive positive pressure support at the initiation of therapy (Davis et al., 2010). Infants randomized early (80%

pH

7.4–7.8

Triglycerides

>110 mg/dL

Cholesterol

65–220 mg/dL

Albumin

1.2–4.1 g/dL

Total protein

2.2–5.9 g/dL

Adapted from Rocha G. Pleural effusions in the neonate. Curr Opin Pulm Med. 2007;13: 305–311.

triglyceride level (usually above serum levels, but not present unless enteral feeds initiated), and high protein content (Table 49.1). The introduction of small-volume fat-containing feeds with resultant elevated fluid triglyceride levels can confirm the diagnosis if biochemical indices are otherwise not confirmatory. A review of 39 cases of pediatric chylothorax revealed that the composition was consistent with previously described classic characteristics (Buttiker et al., 1999). Total cell counts were greater than 1000/mm3 in 92% of cases, and 85% of effusions had greater than 90% lymphocytes (range 57%–89% in 6 additional children). Fluid triglyceride levels were greater than 1.1 mmol/L (98 mg/dL) in all but one case, with values ranging from 0.56 to 26.6 mmol/L (50 to 2358 mg/dL).

Management of Chylothorax Neonatal management of a congenital chylothorax includes replacement of protein, clotting factors, and immunoglobulins as needed. Ongoing respiratory support may be needed, and often a chronic chest drain is required to decrease respiratory compromise. Feeds are usually restricted, either providing medium-chain triglycerides (MCTs) only (because MCTs are generally absorbed directly from the intestine without processing to chylomicrons) or a nonfat diet. If these measures fail, a period of total enteric rest is undertaken, with parenteral nutrition administered, until resolution of the chylous effusion. Some practitioners believe that a period of enteric rest is necessary to decrease strain on the lymphatic system, because lymphatic efflux is still increased even with nonfat-containing diets (Le Coultre, 2003). Once chest drainage has resolved, feeds are reintroduced with a MCT-only formula for 3 to 6 weeks before transitioning to a normal diet. There are no controlled studies demonstrating that one strategy is superior to others to hasten resolution of chylothorax, and in one series, 50% of pediatric chylothoraces resolved with MCT-only diets (Le Coultre et al., 1991). A later series from the same institution had 80% (41 of 51) resolution with conservative, nonoperative management (MCT-only diet or enteric rest) up to 4 weeks’ duration (Beghetti et al., 2000). The primary risk of this approach is infection, because these children have prolonged hospitalizations with central venous access, chest drains, no enteral feeds, and protein and immunoglobulin losses. Eight of 51 children had severe infections in this series. Children who were less likely to have spontaneous

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resolution of chest drainage included those children with elevated central venous pressure, children who had more prolonged effusions, and children with higher output than those with surgical injury. There were more frequent operative interventions in this group (6 of 14 children), which were undertaken only if 4 weeks of conservative therapy failed to decrease drainage to less than10 mL/kg per day (Beghetti et al., 2000). In one series, 4 of 11 children with drainage after 4 weeks resolved their chylothorax by 6 weeks, with 2 of the remaining children too unstable to undergo surgical intervention (Buttiker et al., 1999). An adjunctive medical approach is the administration of somatostatin or its analogue, octreotide, to decrease pleural drainage. Somatostatin is delivered only via continuous infusion, whereas octreotide can also be given via intermittent subcutaneous injection, because of its longer half-life. The mechanism of effect is thought to be via decreased intestinal secretions and absorption and therefore intestinal efflux and abdominal lymphatic return (Kalomenidis, 2006). Some practitioners proceed quickly to the use of these medications, believing they decrease the volume and duration of chest drainage compared with conservative management; however, this has not been studied in a controlled setting, so the efficacy and risks of this approach are unknown (Das and Shah, 2010). Others use these medications once conservative measures have failed. Potential risks of therapy include hormonal effects of glucose instability and hypothyroidism and gastrointestinal (GI) effects such as cholelithiasis, hepatocellular injury, nausea, diarrhea, abdominal distention, and decreased intestinal perfusion. In this regard, monitoring of serum glucose, thyroid function, liver enzymes, and indicators of cholestasis during therapy is recommended. These serious side effects raise concerns, particularly regarding concomitant feeding during administration of the medications. Dosing is either titrated up until chest drainage is minimal (typically starting at 3.5 µg/kg per h and advancing in several steps to 10 µg/kg per h) or started at the higher dose and titrated down once drainage has abated (Helin et al., 2006; Roehr et al., 2006). The infusion is usually continued for several days after chest drainage is controlled and then weaned off over several days. Outcomes using octreotide for congenital chylothoracies have been promising, with several case reports and a recent small case series demonstrating resolution of the chylothorax without adverse effects (Bulbul et al., 2009; Shah and Sinn, 2012). There are reports of recurrence after discontinuation of the medication (Roehr et al., 2006). Most practitioners recommend about 3 to 4 weeks of maximal medical therapy, before proceeding with an operative intervention, while others recommend intervention in patients who drain more than 100 mL/year of age per day without slowing down after 10 to 20 days (Buttiker et al., 1999). Effusions are unlikely to resolve after 6 weeks, and waiting too long for operative intervention may result in significant compromise to the child. Operative interventions include thoracic duct ligation via thoracotomy or thorascopy, pleurodesis, and/or placement of a pleuroperitoneal shunt (Buttiker et al., 1999; Clark et al., 2015; Resch et al., 2016).

Congenital Thoracic Masses and Cysts Fetal lung masses vary in the degree of abnormality of parenchyma and vasculature and probably represent a spectrum of developmental abnormalities that may be difficult to distinguish prenatally (Langston, 2003; Ankermann et al., 2004). In fact, some investigators have suggested classifying these lesions solely on the basis of the vascular supply (systemic vs pulmonary) and whether or not lung structure is normal (Achiron et al., 2004), because the histology

and probably the developmental pathways leading to the individual lesions are overlapping. Some level and degree of fetal airway obstruction have been implicated as the cause of many of these lesions (Langston, 2003). In prenatal series, CPAMs of the lung are frequently the most common lesion reported (Achiron et al., 2004). However, in postnatal series, CPAMs are often less common (with various imaging modalities and pathology available to clarify the diagnosis after birth), particularly when only cystic lesions are considered (Winters and Effmann, 2001; Langston, 2003; Stocker, 2009). There are multiple reports of “hybrid” lesions, with features of both CPAM and bronchopulmonary sequestration (BPS), emphasizing that these lesions constitute a spectrum of anomalies (Winters and Effmann, 2001; Langston, 2003).

Congenital Pulmonary Airway Malformation of the Lung CPAMs are the most common congenital lung lesions and develop from an overgrowth of abnormal lung tissue, extending from different levels of the airway. In general, they are unilateral. The lesions may communicate with the airways, allowing them to transition from being fluid filled in utero to air filled postnatally, but they do not contain normal alveoli. CPAMs were previously known as congenital cystic adenomatoid malformations (CCAMs), which were originally classified into three types based upon the size of the cysts and their cellular characteristics (Stocker et al., 1977). Subsequent revisions of this classification system have included less common proximal and distal lesions and have suggested new nomenclature based on the fact that not all lesions are either adenomatoid or cystic. The term “congenital pulmonary airway malformation” (CPAM), initially proposed by Stocker, has now become the accepted terminology for these lesions (Stocker, 2002). Table 49.2 shows the stages of lung development with the corresponding airway malformation and CPAM type. Consistent with this classification, persistent epithelial expression of the nuclear regulatory protein thyroid transcription factor 1 has been found in type 1 and 3 CPAMs (see later discussion), indicating developmental arrest in the pseudoglandular stage (Morotti et al., 2000), and targeted fetal airway overexpression of the growth factor fibroblast growth factor 10 in rats produces CPAM-like lesions (Gonzaga et al., 2008).

Congenital Pulmonary Airway Malformation Types Type 0 CPAMs originate from the tracheobronchial tree. There is normal lung lobulation, but no formation of alveoli (Stocker, 2002). There are only bronchial-like structures present, indicating an arrest of development in the pseudoglandular stage (Davidson et al., 1998). Lungs may be normal weight or small, but, regardless, this lesion is rapidly lethal because of severe, intractable respiratory failure. The lesion has been termed acinar dysplasia (Rutledge and Jensen, 1986). It is diffuse and bilateral, recurs in families, and can be associated with other anomalies, suggesting a genetic cause (Moerman et al., 1998; Gillespie et al., 2004). In a large pathology series, fewer than 2% of the pulmonary airway malformations were characterized as acinar dysplasia (Stocker, 2002). In contrast, type 1 CPAMs are the most common lesion in postnatal series of airway malformations, identified in 60%–65% of cases (Stocker, 2002, 2009). Cysts are large, usually greater than 2 cm, limited in number, and originate from the distal bronchi or proximal bronchioles (Fig. 49.8A–C). The cysts usually communicate with each other, and they may decrease in size as they drain progressively during advancing gestation. Postnatally, they are aerated, with

CHAPTER 49  Surgical Disorders of the Chest and Airways 

TABLE 49.2 

709

Stages of Airway Branching and Lung Development With Corresponding Congenital Airway Malformation CPAM TYPE

Developmental Stage

Developmental Events

Stocker

Adzick

Embryonic 0–7 weeks

Formation of tracheal bud and growth and branching to segmental bronchi

Type 0 Tracheobronchial Type 1 Bronchial/bronchiolar

Macrocystic

Pseudoglandular 7–17 weeks

Completion of airway branching to terminal bronchioles (preacinar); gland formation

Type 2 Bronchiolar

Canalicular 17–27 weeks

Formation of respiratory bronchioles to prealveolar structures

Type 3 Bronchiolar/alveolar duct

Saccular 28–36 weeks

Formation of secondary septae

Type 4 Distal acinar

Alveolar 36 weeks–2 years

Formation of alveoli

Microcystic

CPAM, Congenital pulmonary airway malformation. From Cha I, Adzick NS, Harrison MR, Finkbeiner WE. Fetal congenital cystic adenomatoid malformations of the lung: a clinicopathologic study of eleven cases. Am J Surg Pathol. 1997;21:537–544; Hislop AA. Airway and blood vessel interaction during lung development. J Anat. 2002;201:325–334.

A

B

C

D

E

F

• Fig. 49.8

  Congenital Pulmonary Airway Malformation. (A) Chest radiograph of an asymptomatic child with a prenatally diagnosed congenital pulmonary airway malformation (CPAM) in the left upper lobe (arrow). (B, C) Axial and coronal computed tomography (CT) images demonstrate a single 3.1 × 2.7-cm cystic lesion in the left upper lobe consistent with a type 1 CPAM. The child underwent uncomplicated left upper lobectomy at 3 months of age. (D) A chest radiograph of an infant with a prenatally diagnosed CPAM that had rapid enlargement of the cystic component, resulting in mediastinal shift and acute respiratory compromise, is shown. (E, F) Axial and coronal CT images show a multicystic mass with cysts ranging from a few millimeters to 1.5 cm consistent with a type 2 CPAM. In the operating room, the patient was found to have a multicystic lesion confined to the left upper lobe with compressive atelectasis of the left lower lobe and underwent left upper lobectomy. (Courtesy of Dr. Chirag V. Patel, Assistant Professor, University of California, Davis Health System, Department of Radiology, Sacramento, CA.)

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fluid also present in some lesions. Type 1 CPAMs are restricted to a single lobe in 95% of the cases. Bilateral lesions are rare. The lesions are lined by a spectrum of respiratory epithelial cells, ranging from cuboidal to ciliated pseudostratified columnar epithelium, and mucus-producing cells may occur in gland-type tissue. The walls of the lesions may resemble walls of bronchi. Respiratory distress depends on the size of the lesion, with some lesions detected only by incidental imaging or following infection or malignant transformation. There does appear to be a risk of malignant transformation in unresected or residual CPAM tissue. The specific link to neoplasm has not been elucidated, though the diagnosis of bronchoalveolar carcinoma (BAC) is made in relatively young patients (10–42 years), and a spectrum of malignancy has been described (MacSweeney et al., 2003; Mani et al., 2007). This is the only CPAM type that is associated with malignancy, and the young age of affected patients suggests that the CPAM lesion is the cause of the malignancy (MacSweeney et al., 2003). Type 2 CPAMs are characterized by multiple, smaller macroscopic cysts, 0.5–2 cm in diameter, which may not be evident by chest radiograph (see Fig. 49.8E–F). These lesions account for 15%–20% of CPAMs. The cysts are lined by respiratory epithelial cells, ranging from cuboidal to columnar in morphology and appear as multiple bronchiole-type structures, although intra-acinar structures may also be interspersed (Rosado-de-Christenson and Stocker, 1991). These lesions are most commonly associated with other anomalies, in 50% of cases, which include severe bilateral renal dysplasia or agenesis, agenesis of other genitourinary structures, sirenomelia, extralobar pulmonary sequestration, and diaphragmatic hernia (Stocker et al., 1977; Stocker, 2009). Conotruncal cardiac malformations have also been described in association with type 1 and type 2 CPAMs (Stocker et al., 1977; Hüsler et al., 2007), and ventricular septal defects have been diagnosed in fetuses and infants with all CPAM types. Type 3 CPAMs are uncommon lesions, occurring in 5%–10% of CPAM cases (Stocker, 2002). These lesions are generally solid, with microscopic cysts (although single larger cysts can be present), and involve an entire lobe or the entire lung. There is often a mass effect in the thorax, and the lesions can cause lung hypoplasia through compression of adjacent structures. The lesions themselves contain bronchiolar and alveolar duct-type morphology with cuboidal epithelium, and there are alveoli-like structures. Type 4 lesions have been more recently described and account for 10% of CPAMs (Stocker, 2002). With large cysts (maximum diameter 7 cm) present, some of these lesions may be mistaken for type 1 CPAMs. They are usually confined to one lobe and tend to be peripheral in location. Infants and children may present with mild respiratory distress, or more severe symptoms if pneumonia occurs, or if the lesion ruptures, causing pneumothorax. However, type 4 CPAMs can also be detected by incidental imaging. These lesions are lined with type I alveolar (flat) and type II (rounded) epithelial cells. The presence of substantial portions of cells representing the more proximal areas of the lung should raise suspicion for pleuropulmonary blastoma (PPB), a distinction that is important (because of malignancy associated with PPB; see later discussion), but one that can be difficult. The approach to diagnose CPAMs in utero has led to a different classification system, based on the natural history of these fetal lesions (see later discussion). Macrocystic CPAMs are defined when a lesion contains cysts that are greater than or equal to 5 mm (types 1 and 2 CPAMs), and microcystic CPAMs are defined as a solid lesion, with cysts less than 5 mm (type 3 CPAMs) (Adzick et al., 1985). Some lesions categorized by these criteria on fetal

ultrasound have been diagnosed as BPS after postnatal resection (Davenport et al., 2004). Fetal Diagnosis and Natural History

Fetal diagnosis of a CPAM is often made when mediastinal shift because of mass effect from the lesion is identified and a cystic, intermediate, or solid mass is detected. This may occur during routine fetal ultrasonography or when the mother is referred for evaluation of polyhydramnios (thought to occur when the mass compresses the esophagus and thus limits fetal swallowing) (Adzick, 2009). A systemic vascular supply identified on imaging is more consistent with a diagnosis of BPS (Winters and Effmann, 2001). Fetal MRI can be used to help distinguish a CPAM from other pulmonary pathology, including BPS and congenital diaphragmatic hernias. In a recent population-based study from the United Kingdom, confirmed CPAMs (postnatal or postmortem) occurred in 9 per 100,000 births, without accounting for lesions that were not further investigated secondary to prenatal resolution (Gornall et al., 2003). In this study, 57% (21 of 37) of fetal CPAMs were confirmed, and 5 cases were missed (prenatal detection rate 21 of 26 [81%]). Generally, growth of CPAM lesions increases until about 28 weeks’ gestation, after which time it plateaus and the lesion regresses in size while the fetus continues to grow (Kunisaki et al., 2007a; Adzick, 2009). Fetal and neonatal problems that arise as the result of a CPAM include the development of nonimmune hydrops and lung hypoplasia, which may be due to compression of the otherwise normally developing lung. Up to one-third of fetuses with a CPAM develop hydrops (Adzick et al., 1998). Factors associated with the development of nonimmune hydrops include an everted ipsilateral hemidiaphragm, predominantly cystic lesions, lesions that exist into the third trimester, and lesions with a CPAM volume ratio (CVR) greater than 1.6 (Vu et al., 2007). The CVR calculates the volume of the mass (length × weight × height × 0.52) divided by the head circumference. With a CVR greater than 1.6, 75% (12 of 16) of fetuses developed hydrops, while only 17% of those with a CVR less than or equal to 1.6 (7 of 42) developed hydrops (Crombleholme et al., 2002). In a series evaluating fetal macrocystic and microcystic lesions, generally the fetuses with microcystic lesions had poorer outcomes, with intrauterine demise or early neonatal death (Adzick et al., 1985). Compared with normal lung, CPAM lesions have unregulated growth, with increased proliferation and decreased apoptosis (Cass et al., 1998), although they are relatively hypovascular (Cangiarella et al., 1995). In fetal CPAM tissue, increased Platelet-Derived Growth Factor subunit B (PDGF-β) and decreased fatty acid binding protein-7 expression have been detected (Liechty et al., 1999; Wagner et al., 2008). Prenatal Management

Initial ultrasound evaluation of the fetus with possible CPAM should include assessment of lesion size with relevant indices, vascular supply, degree of mediastinal shift, ipsilateral diaphragmatic conformation (normal, flat, or everted), polyhydramnios, placentomegaly, and the presence of any other fluid collections (ascites, integumentary edema, pleural or pericardial effusion) indicating the development of fetal hydrops. Additional prenatal evaluation of a fetus with a known CPAM should include a full fetal survey to identify other anomalies, a karyotype, and an echocardiogram, to evaluate for congenital heart disease and to assess cardiac inflow patterns and outputs. These cardiac indices may help identify impending hydrops, mandating closer ultrasound follow-up and repeated echocardiographic measurements. Most referral centers

CHAPTER 49  Surgical Disorders of the Chest and Airways 

recommend at least weekly follow-up ultrasound examinations evaluating lesion size and monitoring for development of hydrops until 28 to 29 weeks’ gestation, at which point regression of the lesion should be occurring. Thereafter, ultrasound evaluations can be spread out to every 2 weeks. Some referral centers have advocated twice-weekly surveillance if the CVR is greater than 1.6, until 28 weeks’ gestation (Adzick, 2009). In a recent series, 21 of 54 fetal lung masses decreased in size or resolved by delivery (Davenport et al., 2004), and a similar proportion of fetal CPAM cases were not detectable at birth in a population-based study (13 of 37, 35%) (Gornall et al., 2003). The diagnosis of hydrops in a fetus with CPAM portends a poor prognosis, with either fetal demise or preterm delivery of a compromised infant (Gornall et al., 2003; Grethel et al., 2007; Kunisaki et al., 2007a). Thus impending or definite hydrops is an indication for fetal intervention. The specific intervention depends on the type of lesion. In fetuses with a macrocystic CPAM, a growing, dominant cyst, and impending or definite hydrops, placement of a thoracoamniotic shunt results in a decrease in cyst size and hemodynamic improvement, with relatively good neonatal survival (12 of 16 in two series) (Adzick et al., 1998; Wilson et al., 2004). However, shunt placement at less than 21 weeks’ gestation may be associated with chest wall deformity, which can compromise later respiratory function, so other interventions may need to be taken at that early gestation (Merchant et al., 2007). Fetal thoracentesis is rarely effective as definitive treatment, because cyst fluid invariably reaccumulates, but it might serve as a temporizing measure until further treatment can be undertaken. For fetuses with impending hydrops and a microcystic CPAM (or failed decompression of a large cyst), open fetal resection (lobectomy or pneumonectomy) improves the chances of survival, although mortality remains high (10 of 23 in one series), and nonsurvivors tended to be more premature (Grethel et al., 2007). This selected approach to fetal resection has resulted in resolution of hydrops and mediastinal shift in survivors (Adzick, 2009). For fetuses greater than 32 weeks’ gestation, or in the case where fetal surgery is contraindicated because of preterm labor, an EXIT-to-resection procedure may provide a chance for survival (Grethel et al., 2007; Adzick, 2009). EXIT procedures have also been undertaken in later-gestation fetuses with persistent large lesions (mean CVR 2.2) despite other fetal interventions, although the impact of this strategy on survival and other outcomes is unknown (Hedrick et al., 2005; Adzick, 2009). Before undertaking any fetal intervention, prenatal glucocorticoid therapy to accelerate fetal lung maturation should be administered. This practice, utilizing betamethasone (12 mg intramuscularly every 24 h × 2 doses), led to the observation that fetuses with microcystic CPAMs (type 3) and hydrops resolved their hydrops after betamethasone exposure (Tsao et al., 2003b). In this series, three fetuses with mild-to-moderate hydrops treated at 21 to 26 weeks’ gestation avoided further fetal interventions, were delivered at term, and survived. This observation led to subsequent studies comparing the use of steroids with open fetal surgery in fetuses with macrocystic CPAMs that demonstrated the effectiveness of steroids in not only halting further growth of a CPAM but also causing regression (Peranteau et al., 2007; Loh et al., 2012). Since this discovery, steroids have become the first line of treatment in fetuses with large microcystic CPAM lesions. Postnatal Management

In fetuses that do not develop hydrops, the overall prognosis is good and probably depends on the type of lesion and the presence

711

of other anomalies. Generally, the prognosis of a type 1 CPAM is good, particularly if fetal intervention is not required. Following resection, there is usually resolution of any symptoms associated with the lesion. Type 2 CPAMs have a worse prognosis, because of the association with additional serious malformations. Type 3 CPAMs are thought to be uniformly lethal from their earliest descriptions and can be associated with lung hypoplasia (Stocker et al., 1977). For fetuses with large microcystic CPAMs, fetal resection, if indicated, may mitigate hypoplasia. However, case series have described substantial spontaneous regression of microcystic CPAMs, with an increased rate of in utero resolution compared with macrocystic lesions (Davenport et al., 2004). In a large series from a single referral center, neonatal survival was 98% (118 of 121) (Grethel et al., 2007). Five infants underwent fetal procedures, with 1 death, and there were 2 neonatal deaths. In a population-based series, there were no postnatal deaths following 20 live births, with a single intrauterine fetal demise and 5 terminations (Gornall et al., 2003). Three fetal interventions (thoracentesis or thoracoamniotic shunt placement) were undertaken in these patients. Approximately 75% of newborns with a prenatally diagnosed CPAM are asymptomatic at birth (Parikh and Rasiah, 2015). The remainder may present with respiratory distress with or without pulmonary hypertension, which can be severe enough to require ECMO support (Kunisaki et al., 2007a; Adzick, 2009). The likelihood of respiratory distress is best predicted by a CVR of greater than 0.84, and the severity of the respiratory distress usually increases as the size of the CPAM increases (Ruchonnet-Metrailler et al., 2014). However, even in a series of large fetal CPAMs (at least 3 cm × 3 cm), only 4 of 9 infants had respiratory distress requiring resection in the first week of life. For newborns with prenatally diagnosed CPAMs, lesions may be detected on chest radiograph, as solid masses, or fluid or air-filled cysts. Mediastinal shift, mass effect, or areas of air trapping due to airway obstruction may be appreciated. Some centers use ultrasound as an adjunctive modality in the neonatal period, but many surgeons prefer a CT scan as the definitive imaging study, which also can detect lesions that are no longer present on fetal ultrasound (Winters and Effmann, 2001). CT scans can also determine if there are multiple bronchopulmonary malformations, which may also require resection, and the use of intravenous contrast allows for definition of the vascular supply, helping to differentiate CPAMs from BPS (Johnson and Hubbard, 2004). For asymptomatic newborns, surgeons will often defer this study until several months of age, because surgical resection is also deferred. The usual surgical approach is lobectomy for the majority of lesions confined to a single lobe. More diffuse lesions might require bilobectomy or pneumonectomy. These surgical approaches are likely to result in the removal of normal lung but may also decrease the risk of air leak and infection after resection (Shanmugam, 2005), and compensatory lung growth does occur after lobectomy (Nakajima et al., 1998). Additional postoperative complications may include prolonged pleural effusion, pneumothorax, pneumonia, and wound infection (Waszak et al., 1999; Kim et al., 2008). The need for resection in asymptomatic newborns remains controversial, and there is no consensus on this topic (Aziz et al., 2004; Singh and Davenport, 2015; Stanton, 2015). Those who argue for watchful waiting cite the risks of surgery and anesthesia, the overtreatment of “nondisease,” and a lack of evidence of the associated malignancy risk as factors for not resecting asymptomatic lesions. Those who argue for intervention say that resection prevents complications of disease, including the risk of malignancy, the

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psychological benefit of removing the lesion, and the improvement in lung volume after resection. In a national survey of Canadian pediatric surgeons, there was not even consensus on whether to resect asymptomatic lesions or not between different surgeons within individual centers (Lo and Jones, 2008). The majority of respondents in this survey (67%) endorsed resecting asymptomatic lesions present on CT, with 78% selecting 2 to 12 months as the age for operation. The concerns about not resecting a lesion are that it remains a persistent nidus for lower respiratory tract infection and that there is the potential for malignant transformation. However, the latter concern is confined to type I CPAMs. A similar study done in the UK found that 24% of surgeons never resect asymptomatic lesions, while 20% always do (Peters et al., 2013). Generally, children who have undergone resection for CPAMs are healthy. Pulmonary function data demonstrate normal vital capacity, residual volume, and expiratory flows between 1 and 2 years post lobectomy (Nakajima et al., 1998). There are some reports of reactive airway disease and lower respiratory tract infection (Kunisaki et al., 2007a) and, in more severely affected children, chronic lung disease and pulmonary hypertension (Keller et al., 2006; Kunisaki et al., 2007a).

Bronchopulmonary Sequestration Bronchopulmonary sequestrations are rare congenital malformations consisting of nonfunctional lung parenchyma that does not have a normal connection to the tracheobronchial tree (Rosado-deChristenson et al., 1993). The lesions have a systemic arterial supply. Sequestrations are categorized into extralobar sequestrations, which are lesions that have their own pleural investment and systemic (80% of the time) venous drainage (and are therefore separate from the lung), and intralobar sequestrations, which are integral to the lung pleura and drain via the pulmonary venous system. Intralobar lesions usually require lobectomy for removal, because they are invested within the lung. The origin of an intralobar sequestration is somewhat controversial. Some experts believe it is not a congenital lung lesion but is rather always acquired after lung infection and injury, because inflammation, fibrosis, and cystic degeneration are its primary pathologic features (Frazier et al., 1997). In a large pathologic series, intralobar lesions usually diagnosed in adulthood and presenting as lower respiratory tract infection account for about 75% of BPS. Others believe that intralobar sequestration can be congenital in origin but is relatively rare in that setting when compared to extrapulmonary sequestration (Winters and Effmann, 2001). Thus the remainder of this discussion focuses on extralobar sequestration. Extralobar sequestrations probably originate as an independent bud from the foregut that derives its blood supply from splanchnic vessels (Rosado-de-Christenson et al., 1993). Usually the connection to the foregut is lost during development, although some lesions have persistent connections to the esophagus or the stomach (also referred to as bronchopulmonary foregut malformations). As accessory lobes, they occur within both the thorax and abdomen. Hybrid lesions with features of both a CPAM and a sequestration can occur (Lopoo et al., 1999; Winters and Effmann, 2001). Extralobar sequestrations are usually situated on the left side (65%–90%), with the most common location between the lower lobe and the hemidiaphragm (approximately 70% of cases). Extrapulmonary BPS can also occur in the abdomen, the mediastinum, the pericardium, and the diaphragm itself. It is more common in males than females (3 to 4 : 1 ratio), and it also commonly occurs in association with other anomalies, including foregut duplication cysts, bronchogenic cysts, CPAMs, pericardial

defects, and ectopic pancreas. In addition, approximately 5% of children with a congenital diaphragmatic hernia will have extralobar sequestration. Histologically, these lesions appear as normal lung, except with dilated airway structures and, commonly, lymphangiectasia. A normal-appearing bronchus is present about 50% of the time. Associated pleural effusions are not uncommon (up to 10% of fetal BPS) and may be secondary to torsion of the vascular pedicle with resultant venous obstruction and elevated pressure or lymphatic abnormalities (Hernanz-Schulman et al., 1991; Johnson and Hubbard, 2004). Fetal diagnosis of intrathoracic BPS is suspected when there is an echogenic mass, which may also contain cysts. Depending on its size, the mass may be associated with some degree of mediastinal shift (Lopoo et al., 1999). It can be difficult to distinguish BPS from a CPAM, but when a systemic arterial supply is identified, the diagnosis of BPS is highly likely. If there is also an associated ipsilateral pleural effusion, the diagnosis is almost certainly BPS (Johnson and Hubbard, 2004). If the diagnosis is still in doubt, fetal MRI can be used to help distinguish between the two (Hubbard et al., 1999). Infradiaphragmatic masses also need to be distinguished from neuroblastoma, other tumors (such as lymphangioma), and adrenal hemorrhage (Curros and Brunelle, 2001; Winters and Effmann, 2001). As with CPAM, BPSs often regress spontaneously over time, and if there are no associated anomalies, the prognosis for the fetus is good (Adzick et al., 1998; Lopoo et al., 1999). Close ultrasound follow-up is prudent, however, until regression is documented. When pleural effusion occurs, there is a risk of development of tension hydrothorax. In these cases, repeated fetal thoracentesis or placement of a thoracoamniotic shunt can avert or resolve hydrops fetalis, which may improve the chances for survival (Lopoo et al., 1999). On postnatal imaging, BPS may be present as a radiographic density on plain film. The presence of linear or cystic lucencies within the radiopaque density suggests a persistent communication between an extralobar sequestration and the GI tract (Leithiser et al., 1986; Laberge et al., 2005). An upper GI study can demonstrate communication with the GI tract and is indicated for surgical planning if feeding difficulties are present. Ultrasound can also be useful in demonstrating the lesion (most easily seen if it is located at the lung base), and Doppler studies can identify a systemic feeding vessel and venous drainage. The use of contrastenhanced CT provides the best visualization of the parenchymal abnormalities but has variable sensitivity for delineation of the vascular supply, although the lesion itself can often be demonstrated even when it has resolved by fetal imaging (Fig. 49.9). Magnetic resonance with angiography can also be useful in demonstrating the lesion and its blood supply. Conventional angiography can identify the vasculature, but this has been replaced by the imaging modalities discussed above (Winters and Effmann, 2001). Symptomatic BPSs are usually identified in the first 6 months of life, with respiratory distress or feeding difficulties. Less commonly, recurrent infection, congestive heart failure (because of a high output state), or pulmonary hemorrhage is present. Distress at birth can be severe, particularly with large lesions complicated by a pleural effusion or hydrops fetalis. For neonates that present with symptoms in the first week of life, early resection is indicated (Azizkhan and Crombleholme, 2008). Because the lesion is completely separate from lung, sequestrectomy is not a complex operation and can be done thorascopically. However, the feeding vessels can be very large in more severe cases, mandating a thoracotomy. The primary risk associated with an unresected BPS is recurrent infection, although this risk is not well quantified, as

CHAPTER 49  Surgical Disorders of the Chest and Airways 

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A B

C • Fig. 49.9

  Bronchopulmonary Sequestration. (A, B) Axial and coronal computed tomography images of an infant with a prenatally diagnosed chest mass (arrows). The mass is located at the left lung base, measuring 3.6 × 3.0 × 2.5 cm. (C) The arterial supply is via a prominent collateral from the descending thoracic aorta at the level of the diaphragm (arrow). The venous drainage is via the azygos vein (not shown). These findings are consistent with an extralobar sequestration. The patient underwent thorascopic resection at 18 months of age. (Courtesy of Dr. Chirag V. Patel, Assistant Professor, University of California, Davis Health System, Department of Radiology, Sacramento, CA.)

there are probably adults with persistent, small, asymptomatic lesions. Consequently, as with CPAM, there is controversy as to whether fetal lesions that are not identified on plain film should be further investigated in asymptomatic infants and, in general, whether asymptomatic lesions should be resected. However, since sequestrectomy can now be accomplished thorascopically at 3 to 15 months, with rapid recovery and short hospitalization (Albanese et al., 2003), most lesions are surgically resected. In addition, this approach may preserve rib architecture and limit later chest wall deformity (Rothenberg and Pokorny, 1992). Early resection, before infectious complications (the primary risk associated with an unresected lesion) may limit complications, because secondary changes such as emphysema might be averted (Rosado-deChristenson et al., 1993). Some have attempted coil embolization of the feeding vessel(s), with hope of complete or partial involution of the lesion (Curros et al., 2000; Chien et al., 2009). However, coil embolization may only result in partial vascular occlusion and incomplete regression, transient lower limb ischemia (because of

distal migration of embolic material), sepsis, and other blood vessel complications. Because of this, thorascopic resection is the current standard of care (Cho et al., 2012).

Other Cystic Lesions Additional cystic lung lesions include congenital lobar emphysema, pleuropulmonary blastoma, and acquired cysts (pneumatoceles or emphysema, in association with infection or BPD, respectively). Extrapulmonary cystic lesions include foregut cysts (bronchogenic or enteric duplication cysts) and neuroenteric cysts, which are less common than the other lesions and usually present later in infancy or childhood (Langston, 2003).

Congenital Lobar Emphysema CLE occurs in 1 to 20,000 to 1 in 30,000 live births (Thakral et al., 2001). Because there is no evidence of lung destruction (true emphysematous changes), the common term CLE is a

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misnomer, with this lesion, which is also known as congenital lobar over inflation (Langston, 2003). CLE is thought to arise from an obstructed lobar bronchus, which can either be intrinsic (including malacia) or extrinsic in origin. While the cause varies, the fundamental mechanism is that air can pass into the effected bronchus but is unable to leave, causing air trapping and lobar overexpansion. The upper lobes are most commonly affected, with the left upper lobe the single most commonly affected lobe. Lesions occupying multiple lobes are infrequent (Mani et al., 2004). Although the affected lobe is larger than usual, the number of alveoli in the involved area is within normal limits. The exception to this is the subset of these lesions with polyalveolar lobe, which was present in 9 of 33 cases of CLE in one series and has an overlapping clinical presentation with CLE (Mani et al., 2004). In polyalveolosis, the total number of alveolar is increased severalfold from normal, but the conducting airways are normal in size and number. This form of lung hyperplasia is consistent with pathophysiology associated with fetal airway obstruction (Langston, 2003). CLE can be detected on fetal ultrasound, although it is difficult to make the correct diagnosis (Olutoye et al., 2000; Babu et al., 2001). Clinical reports have described the appearance of the lesion by ultrasound as cystic and/or echogenic, with mediastinal shift present, and subsequent regression with advancing gestation. As expected, these lesions are suspected to be CPAM or BPS, based on these findings. Fetal MRI can be helpful in characterizing the lesion, although it is not diagnostic (Olutoye et al., 2000). The postnatal clinical presentation and histology (after resection) distinguish CLE from the other lesions. The majority of children with CLE present with respiratory distress, cyanosis, or recurrent pulmonary infections in the first 6 months of life, with 13 of 33 (39%) symptomatic on the first day of life in one series (Mani et al., 2004). The severity of symptoms depends on the size of the affected lobe, the compression of the surrounding tissue, and the extent of mediastinal shift. Chest radiographs demonstrate a hyperinflated lung (transitioning from fluid filled to air filled over the initial postnatal days), with compression of other areas of the lung and mediastinal shift (Fig. 49.10). These findings are generally diagnostic. In children with less severe presentation, bronchoscopy or CT scan can be helpful in management decisions, because some surgeons will elect to manage these patients expectantly, with resolution of symptoms in some cases (Stigers et al., 1992). After resection, prognosis is generally good, with compensatory lung growth present on the affected side (McBride et al., 1980). Airway obstruction continues to be a feature of the disease on pulmonary function tests, although these findings could be consistent with either compensatory lung growth exceeding airway growth (dysanapsis) or intrinsic, diffuse airway abnormality.

Pleuropulmonary Blastoma Pleuropulmonary blastoma (PPB) is a rare but malignant lesion arising from the lung or the pleura. Lesions can be predominantly cystic (type I), mixed cystic and solid (type II), or predominantly solid type (III) and can occur in association with other congenital lung lesions. The average age of diagnosis of type I, II, and III PPBs is 10 months, 34 months, and 44 months, respectively, and overall survival of type I PPBs is 80%–85%, while survival in type II and IIII patients is 45%–50% (Priest et al., 1996). The diagnosis and resection of this lesion are essential, because of the risk of metastasis, recurrence, and associated malignancies (Priest et al., 1996). Although these lesions tend to present later in childhood than CPAMs, there is overlap in the timing of presentation (Stocker, 2002), and PPB can be detected on fetal ultrasound (Miniati et al.,

2006); thus the consideration of this diagnosis in the perinatal period is relevant for counseling and surveillance, even if a newborn is not symptomatic. Symptomatic infants usually present with respiratory distress. Before resection, most lesions are thought to be CPAMs, based on their appearance on fetal ultrasound or postnatal CT scan (Miniati et al., 2006). The treatment of choice for PPBs is surgical resection. While type II and type III lesions have been treated with adjuvant chemotherapy given their aggressive nature, there are increasing data to suggest adjuvant chemotherapy will reduce reoccurrence in type I patients as well (Miniati et al., 2006). Patients with type II and III lesions with residual disease following resection should also be treated with radiation therapy (Parsons et al., 2001). Resected lesions contain cuboidal or columnar epithelial cells with underlying rhabdomyosarcoma cells (or other sarcomas). The malignant cells may not be widespread in the lesion, making the diagnosis of PPB challenging even by histology (Stocker, 2002, 2009; Hill and Dehner, 2004). Because of the difficulty in distinguishing CPAMs from PPBs, careful histologic evaluation of prophylactically resected CPAMs is recommended, as those with stellate and spindle cells should be followed closely (Papagiannopoulos et al., 2001). Furthermore, PPBs may require a more extensive resection than CPAMs, so this distinction is important in determining surgical approach as well (MacSweeney et al., 2003). Tumor cells often have complex chromosomal rearrangements, and affected children can exhibit other neoplastic diseases: medullablastoma, nephroblastoma, thyroid dysplasia and malignancy, and brain sarcoma (Priest et al., 1996; Stocker, 2002). Kindreds also demonstrate multiple malignancies, suggesting that familial surveillance for disease might be indicated (Priest et al., 1996).

Postinfectious Pneumatoceles Pneumatoceles are thin-walled, air-containing cystic structures resulting from alveolar and bronchiolar necrosis. In our experience, the most common infection associated with pneumatoceles in the newborn (maybe because of its higher frequency of infection) is Staphylococcus aureus pneumonia (Imamoglu et al., 2005). Other infections seen in the NICU that are associated with development of pneumatocele include pneumonia caused by Actinomyces and Candida species, Pseudomonas aeruginosa, and Klebsiella pneumoniae (Stocker, 2009). Pneumatoceles are often present on initial chest radiograph documenting the infiltrate, although they can also occur later in the process. Given the thin wall, pneumatoceles can rupture, resulting in a pneumothorax that may be under tension or compress the lung tissue through mass effect, resulting in worsening respiratory status (Kunyoshi et al., 2006). Acutely, urgent interventions may be needed to improve ventilation and oxygenation in the setting of rupture. Placement of chest drains into the pneumatocele(s) in the absence of rupture, either percutaneously or under direct visualization via VATS, can be considered; however, the majority of these cysts are regressive and resolve spontaneously (Kunyoshi et al., 2006; Fujii and Moulton, 2008) (Fig. 49.11). For patients with chronic ventilator dependence, in particular former premature infants with BPD, resection of the affected lobe could be considered (Al-Saleh et al., 2008). Hyperinflation and Emphysema in Chronic Lung Disease Similar to postinfectious pneumatoceles, frank cysts or hyperinflated lung may develop in association with chronic lung disease of prematurity (BPD) or with certain developmental lung abnormalities. This cystic hyperinflation can cause compression of more functional areas of the lung, with consequent respiratory compromise

CHAPTER 49  Surgical Disorders of the Chest and Airways 

A

B

C

D

715

• Fig. 49.10  Congenital Lobar Emphysema. (A) Chest radiograph showing significant hyperinflation of the right lung with mediastinal shift to the left. (B) Coronal chest computed tomography demonstrating hyperaeration of the right middle lobe consistent with congenital lobar emphysema right sided. (C) Intraoperative photo showing the right middle lobe characteristically “popping out” of the thoracotomy incision prior to resection. (D) Chest radiograph 3 days after right middle lobe resection showing normalization of lung volume on the right with resolution of mediastinal shift. (A, B, and D, Courtesy of Dr. Chirag V. Patel, Assistant Professor, University of California, Davis Health System, Department of Radiology, Sacramento, CA. C, Courtesy of Dr. Clifford C. Marr, Clinical Professor, Sutter Medical Group, Department of Surgery, Division of Pediatric Surgery, Sutter Medical Center, Sacramento, CA.) (Moylan and Shannon, 1979; Stocker, 2009). While this very severe chronic lung disease complication of prematurity rarely occurs today, affected infants can acutely decompensate or remain ventilator dependent despite maximal medical therapy. Evaluation of 6 infants with BPD and decompensated lobar hyperinflation in one series revealed extensive lobar bronchomalacia, with almost complete collapse of the affected airway through the expiratory phase or the entire respiratory cycle (Azizkhan et al., 1992). Lobectomy results in acute improvement, although ultimately only half of infants who are so treated survive.

Miscellaneous Cysts Lymphatic, lymphangiomatous, mesothelial, and parenchymal cysts can be detected in the thorax, so these lesions may need to be included in the differential diagnosis of cystic lesions (Langston, 2003).

Disorders of the Diaphragm Congenital Diaphragmatic Hernia Congenital diaphragmatic hernia (CDH) is a disorder of lung and pulmonary vascular hypoplasia that results from failure of formation of the diaphragm (Areechon and Eid, 1963; Kitagawa et al., 1971; Hislop and Reid, 1973). This may be due to primary deficiency of the embryonic pleuroperitoneal fold, which is one of the critical primordial diaphragmatic structures that must fuse at 6 to 8 weeks’ gestation to form an intact diaphragm (Clugston et al., 2006). Failure of this event results in herniation of abdominal contents into the hemithorax, and the subsequent arrest of preacinar airway branching at 10 to 14 weeks’ gestation is consistent with this early developmental defect. Hypoplasia is bilateral, although the lung ipsilateral to the hernia is most affected. Airway diameter is

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• Fig. 49.11

  Postinfectious Pneumatoceles. Chest radiographs from a former preterm infant with pneumatoceles secondary to Staphylococcus aureus pneumonia. Cysts are compressing the lung and causing mediastinal shift (left). Placement of draining thoracostomy tubes decompressed the cysts and decreased mediastinal shift, but the infant ultimately succumbed to respiratory failure secondary to bronchopulmonary dysplasia.

substantially decreased, but increase in airway muscle occurs as a later postnatal event (Broughton et al., 1998). Although acinar alveolar counts are normal, overall alveolar hypoplasia is present due to the branching defect (